Aryl- and Heteroarylcarbonyl derivatives of substituted nortropanes, medicaments containing such compounds and their use

ABSTRACT

The present invention relates to compounds defined by formula (I) wherein the groups R 1  and R 2  are defined as in claim  1 , possessing valuable pharmacological activity. Particularly the compounds are inhibitors of 11 β-hydroxysteroid dehydrogenase (HSD) 1 and thus are suitable for treatment and prevention of diseases which can be influenced by inhibition of this enzyme, such as metabolic diseases, in particular diabetes type 2, obesity, and dyslipidemia.

The present invention relates to compounds derived from the followingchemical scaffold which is structurally defined by the formula I

wherein the groups R¹ and R² are as defined hereinafter, including thetautomers, the stereoisomers, the mixtures thereof and the saltsthereof. The invention further relates to pharmaceutical compositionscontaining a compound of formula I according to the invention as well asthe use of a compound according to the invention for preparing apharmaceutical composition for the treatment of metabolic disorders. Inaddition, the invention relates to processes for preparing apharmaceutical composition as well as a compound according to theinvention.

In the literature, compounds which have an inhibitory effect on theenzyme 11β-hydroxysteroid dehydrogenase (HSD) 1 are proposed for thetreatment of the metabolic syndrome, in particular diabetes type 2,obesity, and dyslipidemia.

In the international application WO 2006/044174 derivatives ofnortropanes of the general formula

wherein R², R³, R⁴, W, Y¹ to Y⁵, W, T, U, P, Q, and X are as definedtherein, are described as ligands of the melanin concentrating hormone(MCH) receptor which may be used to modulate MCH binding to MCHreceptors.

AIM OF THE INVENTION

The aim of the present invention is to find new nortropanes,particularly those which are active with regard to the enzyme11β-hydroxysteroid dehydrogenase (HSD) 1. A further aim of the presentinvention is to discover nortropanes which have an inhibitory effect onthe enzyme 11 β-hydroxysteroid dehydrogenase (HSD) 1 in vitro and/or invivo and possess suitable pharmacological and pharmacokinetic propertiesto use them as medicaments.

A further aim of the present invention is to provide new pharmaceuticalcompositions which are suitable for the prevention and/or treatment ofmetabolic disorders, particularly diabetes, obesity, and dyslipidemia.

Other aims of the present invention will become apparent to the skilledman directly from the foregoing and following remarks.

OBJECT OF THE INVENTION

In a first aspect the present invention relates to compounds which arestructurally defined by the formula I

wherein

-   R¹ denotes phenyl, naphthyl,    -   pyrrolyl, furanyl, thienyl, pyridinyl, indolyl, benzofuranyl,        benzothiophenyl, quinolinyl,    -   isoquinolinyl, or    -   pyrrolyl, imidazolyl, furanyl, thienyl, pyridinyl, in each of        which one or two CH groups are replaced by N, or    -   indolyl, benzofuranyl, benzothiophenyl, quinolinyl,        isoquinolinyl, in each of which 1 to 3 CH groups are replaced by        N, or    -   pyrazolopyrimidinyl, triazolopyrimidinyl,    -   while in the above-mentioned N-heteroaromatic groups one or two        —N═CH— groups are optionally replaced by —NH—CO— and/or        —N(C₁₋₄-alkyl)—CO—, and    -   while the above-mentioned polycyclic aromatic and heteroaromatic        groups are optionally partially saturated, though, retaining an        aromatic or heteroaromatic substructure that is attached to the        carbonyl group in formula I,        -   where in the partially saturated rings one or two CH₂ groups            optionally are independently replaced by oxygen, sulfur, NH,            N(C₁₋₄-alkyl), carbonyl, or sulfonyl,    -   wherein the above-mentioned aromatic, heteroaromatic, partially        saturated aromatic and heteroaromatic groups are optionally        substituted with one or more, preferably one to four,        substituents R⁴, and wherein 2 adjacent C-atoms of each of said        rings are optionally substituted with R⁵ and R⁶, and    -   wherein all heteroaromatic rings are attached to the carbonyl        group in formula I via a carbon atom,-   R² denotes phenyl, naphthyl,    -   pyrrolyl, furanyl, thienyl, pyridinyl, indolyl, benzofuranyl,        benzothiophenyl, quinolinyl,    -   isoquinolinyl, or    -   pyrrolyl, imidazolyl, furanyl, thienyl, pyridinyl, in each of        which one or two CH groups are replaced by N, or indolyl,        benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, in        each of which 1 to 3 CH groups are replaced by N,    -   while the above-mentioned aromatic and heteroaromatic groups are        optionally substituted with one or more, preferably one to four,        substituents R⁷,    -   wherein all heteroaromatic rings are attached to the nortropane        skeleton in formula I via a carbon atom,-   R⁴ independently of each other denotes halogen, C₁₋₆-alkyl,    C₂₋₆-alkenyl, C₂₋₆-alkynyl, hydroxy, C₁₋₄-alkyloxy,    -   nitro, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino,        pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, piperidin-1-yl,        2-oxo-piperidin-1-yl, morpholin-4-yl, 3-oxo-morpholin-4-yl,        piperazin-1-yl, 2-oxo-piperazin-1-yl, 3-oxo-piperazin-1-yl,        4-(C₁₋₃-alkyl)piperazin-1-yl,        4-(C₁₋₄-alkylcarbonyl)-piperazin-1-yl,        4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkyl-oxycarbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl,        2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,        3-oxo-4-(C₁₋₃-alkyl)piperazin-1-yl,    -   C₁₋₃-alkyl-carbonylamino, (het)aryl-carbonylamino,        (het)aryl-C₁₋₃-alkyl-carbonylamino, C₁₋₃-alkyloxy-carbonylamino,        aminocarbonylamino, C₁₋₃-alkyl-aminocarbonylamino,        di-(C₁₋₃-alkyl)aminocarbonylamino,        pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonyl-amino,        morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino,        4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonylamino,        C₁₋₃-alkyl-sulfonylamino, aminosulfonylamino,        C₁₋₃-alkylamino-sulfonylamino,        di-(C₁₋₃-alkyl)amino-sulfonylamino,        pyrrolidin-1-yl-sulfonyl-amino, piperidin-1-yl-sulfonylamino,        morpholin-4-yl-sulfonylamino, piperazin-1-yl-sulfonylamino,        4-(C₁₋₃-alkyl)piperazin-1-yl-sulfonylamino,        (C₁₋₃-alkyloxy-carbonyl-amino)carbonylamino,        (het)arylsulfonylamino, (het)aryl-C₁₋₃-alkyl-sulfonylamino,    -   N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-carbonylamino,        N—(C₁₋₃-alkyl)-(het)arylcarbonylamino,        N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkyl-carbonylamino,        N—(C₁₋₃-alkyl)-C₁₋₃-alkyloxy-carbonylamino,        N-(aminocarbonyl)-C₁₋₃-alkylamino,        N—(C₁₋₃-alkylaminocarbonyl)-C₁₋₃-alkylamino,        N—[di-(C₁₋₃-alkyl)aminocarbonyl]-C₁₋₃-alkylamino,    -   N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-sulfonylamino,        N—(C₁₋₃-alkyl)-(het)arylsulfonylamino,        N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkyksulfonylamino,    -   oxo-imidazolidin-1-yl, 2,4-dioxo-imidazolidin-1-yl,        2,5-dioxo-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl,        wherein the nitrogen atom in position 3 of the aforementioned        groups is optionally substituted with methyl or ethyl,    -   1,1-dioxothiazinanyl,    -   cyano, carboxy, C₁₋₃-alkyloxy-carbonyl, aminocarbonyl,        C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,        pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,        morpholin-4-yl-carbonyl, piperazin-1-yl-carbonyl,        4-(C₁₋₃-alkyl)piperazin-1-yl-carbonyl, (het)aryl-aminocarbonyl,        N—(C₁₋₃-alkyl)-(het)arylaminocarbonyl,        (het)aryl-C₁₋₃-alkylamino-carbonyl,        N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkylaminocarbonyl,    -   C₁₋₄-alkyl-carbonyl, (het)aryl-carbonyl,    -   C₁₋₃-alkylcarbonyl-C₁₋₃-alkyl, carboxy-C₁₋₃-alkyl,        C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyl, cyano-C₁₋₃-alkyl,        aminocarbonyl-C₁₋₃-alkyl, C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyl,        di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl,        pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl,        piperidin-1-yl-carbonyl-C₁₋₃-alkyl,        morpholin-4-yl-carbonyl-C₁₋₃-alkyl,        piperazin-1-yl-carbonyl-C₁₋₃-alkyl,        4-(C₁₋₃-alkyl)piperazin-1-yl-carbonyl-C₁₋₃-alkyl,    -   carboxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyloxy,        cyano-C₁₋₃-alkyloxy, aminocarbonyl-C₁₋₃-alkyloxy,        C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyloxy,        di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy,        pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl-oxy,        piperidin-1-yl-carbonyl-C₁₋₃-alkyloxy,        morpholin-4-yl-carbonyl-C₁₋₃-alkyl-oxy,        piperazin-1-yl-carbonyl-C₁₋₃-alkyloxy,        4-(C₁₋₃-alkyl)piperazin-1-yl-carbonyl-C₁₋₃-alkyloxy,    -   hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl,        C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,        pyrrolidin-1-yl-C₁₋₃-alkyl, 2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl,        piperidin-1-yl-C₁₋₃-alkyl, 2-oxo-piperidin-1-yl-C₁₋₃-alkyl,        morpholin-4-yl-C₁₋₃-alkyl, 3-oxo-morpholin-4-yl-C₁₋₃-alkyl,        piperazin-1-yl-C₁₋₃-alkyl, 2-oxo-piperazin-1-yl-C₁₋₃-alkyl,        3-oxo-piperazin-1-yl-C₁₋₃-alkyl,        4-(C₁₋₃-alkyl)piperazin-1-yl-C₁₋₃-alkyl,        2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,        3-oxo-4-(C₁₋₃-alkyl)piperazin-1-yl-C₁₋₃-alkyl,    -   C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl,        arylcarbonylamino-C₁₋₃-alkyl,    -   hydroxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-C₁₋₃-alkyloxy,        C₁₋₃-alkylsulfanyl-C₁₋₃-alkyloxy,        C₁₋₃-alkylsulfinyl-C₁₋₃-alkyloxy,        C₁₋₃-alkylsulfonyl-C₁₋₃-alkyloxy, amino-C₁₋₃-alkyloxy,        C₁₋₃-alkylamino-C₁₋₃-alkyloxy,        di-(C₁₋₃-alkyl)amino-C₁₋₃-alkyloxy,        pyrrolidin-1-yl-C₁₋₃-alkyloxy,        2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyloxy,        piperidin-1-yl-C₁₋₃-alkyloxy,        2-oxo-piperidin-1-yl-C₁₋₃-alkyloxy,        morpholin-4-yl-C₁₋₃-alkyloxy,        3-oxo-morpholin-4-yl-C₁₋₃-alkyloxy,        piperazin-1-yl-C₁₋₃-alkyloxy,        2-oxo-piperazin-1-yl-C₁₋₃-alkyloxy,        3-oxo-piperazin-1-yl-C₁₋₃-alkyloxy,        4-(C₁₋₃-alkyl)piperazin-1-yl-C₁₋₃-alkyloxy,        2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyloxy,        3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyloxy,    -   C₁₋₃-alkylsulfanyl, C₁₋₃-alkylsulfinyl, C₁₋₃-alkylsulfonyl,        C₁₋₃-alkylsulfonyloxy, (het)arylsulfonyl, (het)arylsulfonyloxy,        trifluoromethylsulfanyl, trifluoromethylsulfinyl,        trifluoromethylsulfonyl,    -   aminosulfonyl, C₁₋₃-alkyl-aminosulfonyl,        di-(C₁₋₃-alkyl)-aminosulfonyl, pyrrolidin-1-yl-sulfonyl,        piperidin-1-yl-sulfonyl, morpholin-4-yl-sulfonyl,        piperazin-1-yl-sulfonyl, 4-(C₁₋₃-alkyl)piperazin-1-yl-sulfonyl,    -   difluoromethyl, trifluoromethyl, difluoromethoxy,        trifluoromethoxy,    -   2,2,2-trifluoro-1-hydroxyethyl,        2,2,2-trifluoro-1-hydroxy-1-methylethyl,        2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl,    -   C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyloxy,    -   C₃₋₆-cycloalkyl-C₁₋₃-alkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyloxy,    -   (het)aryl, (het)aryloxy, (het)aryl-C₁₋₃-alkyl,        (het)aryl-C₁₋₃-alkyloxy, (het)aryloxy-C₁₋₃-alkyl, or    -   tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,        tetrahydropyran-4-yloxy, tetra-hydrofuranyl-C₁₋₃-alkyloxy,        tetrahydropyranyl-C₁₋₃-alkyloxy, thietan-3-yloxy,    -   while the above-mentioned C_(3-n)-cycloalkyl and        C_(3-n)-cycloheteroalkyl groups are optionally substituted with        one or two groups independently selected from fluorine,        C₁₋₃-alkyl, C₁₋₃-alkoxy, C₁₋₃-alkoxy-C₁₋₃-alkyl, or hydroxy, and        wherein one CH₂ group is optionally replaced by CO or SO₂, and-   R⁵ and R⁶ are linked to each other and bound to adjacent carbon    atoms and form together a methylenedioxy, ethylenedioxy, or    C₃₋₅-alkylene bridging group, which may be mono- or disubstituted    with fluorine and/or methyl; or-   R⁵ and R⁶ may form combined with the carbon atoms they are attached    to a benzo, pyrido, pyrimido, pyrrolo, furano, thieno, pyrazolo,    imidazo, oxazolo, thiazolo, isoxazolo, or isothiazolo ring, wherein    each of said rings is optionally substituted with one or more,    preferably one to four, substituents independently of each other    selected from halogen, C₁₋₃-alkyl, trifluoromethyl, amino,    C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino, C₁₋₃-alkylcarbonylamino,    hydroxy, cyano, carboxy, C₁₋₃-alkyloxycarbonyl, and C₁₋₃-alkyloxy,-   R⁷ independently of each other denotes halogen, nitro, cyano,    hydroxy, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyloxy,    tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,    tetrahydropyran-4-yloxy, tetrahydrofuranyl-C₁₋₃-alkyloxy,    tetrahydropyranyl-C₁₋₃-alkyloxy, (het)aryl, (het)aryloxy,    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₄-alkyloxy, where in        each group optionally one CH₂ group is replaced by carbonyl or        sulfonyl and each of which is optionally mono- or        polyfluorinated and optionally mono- or disubstituted with        -   hydroxy, chlorine, C₁₋₃-alkyloxy, amino, C₁₋₃-alkylamino,            di-(C₁₋₃-alkyl)-amino, pyrrolidin-1-yl,            2-oxo-pyrrolidin-1-yl, piperidin-1-yl, 2-oxo-piperidin-1-yl,            morpholin-4-yl, 3-oxo-morpholin-4-yl, piperazin-1-yl,            2-oxo-piperazin-1-yl, 3-oxo-piperazin-1-yl,            4-(C₁₋₃-alkyl)piperazin-1-yl,            2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,            3-oxo-4-(C₁₋₃-alkyl)piperazin-1-yl, carboxy,            C₁₋₃-alkyloxy-carbonyl, cyano, aminocarbonyl,            C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,            pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,            morpholin-4-yl-carbonyl, piperazin-1-yl-carbonyl,            4-(C₁₋₃-alkyl)piperazin-1-yl-carbonyl,            C₁₋₃-alkyl-carbonylamino, arylcarbonylamino,            C₁₋₃-alkylsulfanyl, C₁₋₃-alkylsulfinyl, C₁₋₃-alkylsulfonyl,            C₃₋₆-cycloalkyl, (het)aryl, or (het)aryloxy;    -   amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino, pyrrolidin-1-yl,        2-oxo-pyrrolidin-1-yl, piperidin-1-yl, 2-oxo-piperidin-1-yl,        morpholin-4-yl, 3-oxo-morpholin-4-yl, piperazin-1-yl,        2-oxo-piperazin-1-yl, 3-oxo-piperazin-1-yl,        4-(C₁₋₃-alkyl)piperazin-1-yl,        4-(C₁₋₄-alkylcarbonyl)-piperazin-1-yl,        4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkyloxycarbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl,        2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,        3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,    -   C₁₋₄-alkyl-carbonylamino, (het)aryl-carbonylamino,        (het)aryl-C₁₋₃-alkyl-carbonylamino, C₁₋₃-alkyloxy-carbonylamino,        aminocarbonylamino, C₁₋₃-alkyl-aminocarbonylamino,        di-(C₁₋₃-alkyl)aminocarbonylamino,        pyrrolidin-1-yl-carbonyl-amino, piperidin-1-yl-carbonylamino,        morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino,        4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonylamino,        C₁₋₃-alkyl-sulfonylamino, aminosulfonylamino,        C₁₋₃-alkylamino-sulfonylamino,        di-(C₁₋₃-alkyl)amino-sulfonylamino,        pyrrolidin-1-yl-sulfonyl-amino, piperidin-1-yl-sulfonylamino,        morpholin-4-yl-sulfonylamino, piperazin-1-yl-sulfonylamino,        4-(C₁₋₃-alkyl)piperazin-1-yl-sulfonylamino,        (C₁₋₃-alkyloxy-carbonyl-amino)carbonylamino,        (het)arylsulfonylamino, (het)aryl-C₁₋₃-alkyl-sulfonylamino,    -   N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-carbonylamino,        N—(C₁₋₃-alkyl)-(het)arylcarbonylamino,        N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkyl-carbonylamino,        N—(C₁₋₃-alkyl)-C₁₋₃-alkyloxy-carbonylamino,    -   N-(aminocarbonyl)-C₁₋₃-alkylamino,        N—(C₁₋₃-alkylaminocarbonyl)-C₁₋₃-alkylamino,        N-[di-(C₁₋₃-alkyl)aminocarbonyl]-C₁₋₃-alkylamino,    -   N—(C₁₋₃-alkyl)-C₁₋₃-alkylsulfonylamino,        N—(C₁₋₃-alkyl)-(het)arylsulfonylamino,        N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkyksulfonylamino,    -   carboxy, C₁₋₃-alkyloxy-carbonyl, aminocarbonyl,        C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,        pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,        morpholin-4-yl-carbonyl, piperazin-1-yl-carbonyl,        4-(C₁₋₃-alkyl)piperazin-1-yl-carbonyl, (het)aryl-aminocarbonyl,        N—(C₁₋₃-alkyl)-(het)arylaminocarbonyl,        (het)aryl-C₁₋₃-alkylamino-carbonyl,        N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkylaminocarbonyl,    -   C₁₋₃-alkylsulfanyl, C₁₋₃-alkysulfinyl, (het)arylsulfonyl,        trifluoromethylsulfanyl, trifluoromethylsulfinyl,    -   aminosulfonyl, C₁₋₃-alkyl-aminosulfonyl,        di-(C₁₋₃-alkyl)-aminosulfonyl, pyrrolidin-1-yl-sulfonyl,        piperidin-1-yl-sulfonyl, morpholin-4-yl-sulfonyl,        piperazin-1-yl-sulfonyl, 4-(C₁₋₃-alkyl)piperazin-1-yl-sulfonyl,    -   wherein the above-mentioned C_(3-n)-cycloalkyl and        C_(3-n)-cycloheteroalkyl groups are optionally substituted with        one or two groups independently selected from fluorine,        C₁₋₃-alkyl, C₁₋₃-alkoxy, C₁₋₃-alkoxy-C₁₋₃-alkyl, or hydroxy, and        wherein one CH₂ group is optionally replaced by CO or SO₂, and-   R¹¹ independently of each other denotes halogen, C₁₋₄-alkyl,    difluoromethyl, trifluoromethyl, cyano, nitro, amino,    C₁₋₃-alkylcarbonylamino, C₁₋₃-alkylsulfonylamino, carboxy,    C₁₋₄-alkyloxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,    di-(C₁₋₃-alkyl)-aminocarbonyl, aminosulfonyl,    C₁₋₃-alkylaminosulfonyl, di-(C₁₋₃-alkyl)-aminosulfonyl,    C₁₋₃-alkylsulfanyl, C₁₋₃-alkylsulfinyl, C₁₋₃-alkylsulfonyl, hydroxy,    C₁₋₃-alkyloxy, difluoromethoxy, trifluoromethoxy, phenyl,    while the above-mentioned (het)aryl is phenyl, naphthyl, pyrrolyl,    furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl,    quinolinyl, isoquinolinyl, or pyrrolyl, furanyl, thienyl,    imidazolyl, pyridyl in which 1 or 2 CH are replaced by N, or    indolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl in    which 1 to 3 CH are replaced by N, or    a ring selected from the group consisting of    1,2-dihydro-2-oxo-pyridinyl, 1,4-dihydro-4-oxo-pyridinyl,    2,3-dihydro-3-oxo-pyridazinyl,    1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl,    1,2-dihydro-2-oxo-pyrimidinyl, 3,4-dihydro-4-oxo-pyrimidinyl,    1,2,3,4-tetrahydro-2,4-dioxo-pyrimidinyl,    1,2-dihydro-2-oxo-pyrazinyl, 1,2,3,4-tetrahydro-2,3-dioxo-pyrazinyl,    2,3-dihydro-2-oxo-indolyl, 2,3-dihydrobenzofuranyl,    2,3-dihydro-2-oxo-1H-benzimidazolyl, 2,3-dihydro-2-oxo-benzoxazolyl,    1,2-dihydro-2-oxo-quinolinyl, 1,4-dihydro-4-oxo-quinolinyl,    1,2-dihydro-1-oxo-isoquinolinyl, 1,4-dihydro-4-oxo-cinnolinyl,    1,2-dihydro-2-oxo-quinazolinyl, 1,4-dihydro-4-oxo-quinazolinyl,    1,2,3,4-tetrahydro-2,4-dioxo-quinazolinyl,    1,2-dihydro-2-oxoquinoxalinyl,    1,2,3,4-tetrahydro-3-oxo-quinoxalinyl,    1,2,3,4-tetrahydro-2,3-dioxo-quinoxalinyl,    1,2-dihydro-1-oxo-phthalazinyl,    1,2,3,4-tetrahydro-1,4-dioxo-phthalazinyl, chromanyl, coumarinyl,    2,3-dihydro-benzo[1,4]dioxinyl and    3,4-dihydro-3-oxo-2H-benzo[1,4]oxazinyl,    wherein each above-mentioned (het)aryl is optionally substituted    with 1, 2 or 3 R¹¹ which may be identical or different,    whilst the above-mentioned alkyl or alkylene moieties may be    branched or unbranched,    the tautomers thereof, the stereoisomers thereof, the mixtures    thereof, and the salts thereof.

A preferred embodiment of this invention is described by formula I,wherein R¹ denotes

-   -   phenyl, naphthyl, pyrrolyl, furanyl, thienyl, pyridinyl,        indolyl, benzofuranyl, benzothio phenyl, quinolinyl,        isoquinolinyl, or    -   pyrrolyl, furanyl, thienyl, pyridinyl wherein 1 or 2 CH are        replaced by N, or    -   indolyl, benzofuranyl, benzothiophenyl, quinolinyl,        isoquinolinyl, wherein 1 or 2 CH are replaced by N, or    -   indolinyl, 2-oxo-2,3-dihydro-indolyl,        1-oxo-2,3-dihydro-isoindolyl, 2-oxo-2,3-dihydro-benzoimidazolyl,        pyrazolo[1,5-a]pyrimidinyl,        7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidinyl,        [1,2,4]triazolo[1,5-a]pyrimidinyl,        4-oxo-3,4-dihydro-quinazolinyl, tetrahydroquinolinyl,    -   wherein the above-mentioned aromatic and heteroaromatic groups        are optionally substituted with one or more, preferably one to        four, substituents R⁴ and wherein 2 adjacent C-atoms are        optionally substituted with R⁵ and R⁶.

Another preferred embodiment of this invention is described by formulaI, wherein R¹ denotes phenyl, naphthyl, furanyl, thienyl, pyrazolyl,oxazolyl, thiazolyl, isothiazolyl, [1,2,5]-thiadiazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, indolyl, indolinyl,2-oxo-2,3-dihydro-indolyl, 1-oxo-2,3-dihydro-isoindolyl, indazolyl,benzimidazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl, benzoxazolyl,benzotriazolyl, benzothiazolyl, pyrazolo[1,5-a]pyrimidinyl,7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidinyl, quinoxalinyl, quinolinyl,isoquinolinyl, quinazolinyl, 4-oxo-3,4-dihydro-quinazolinyl,naphthyridinyl, and 1,2,3,4-tetrahydroquinolinyl, each of these groupsis optionally substituted with one or more, preferably one to four,substituents R⁴ and/or at 2 adjacent C-atoms with R⁵ and R⁶.

Another preferred embodiment of this invention is described by formulaI, wherein R¹ denotes phenyl, furanyl, thienyl, pyrazolyl, thiazolyl,pyridinyl, benzofuranyl, indolyl, indolinyl,2-oxo-2,3-dihydro-1H-indolyl, 1-oxo-2,3-dihydro-1H-isoindolyl,indazolyl, benzimidazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl,benzotriazolyl, benzothiazolyl, quinoxalinyl, quinolinyl, isoquinolinyl,4-oxo-3,4-dihydro-quinazolinyl, and 1,2,3,4-tetrahydroquinolinyl, eachof these groups is optionally substituted with one to four substituentsR⁴ and/or at 2 adjacent C-atoms with R⁵ and R⁶.

Another preferred embodiment of this invention is described by formulaI, wherein R¹ denotes phenyl, benzofuranyl, indolyl,2-oxo-2,3-dihydro-1H-indolyl, indazolyl, benzimidazolyl, benzotriazolyl,benzothiazolyl, quinoxalinyl, quinolinyl, and1,2,3,4-tetrahydroquinolinyl, each of these groups is optionallysubstituted with one, two, or three substituents R⁴ or optionallysubstituted with one or two substituents R⁴ and/or at 2 adjacent C-atomswith R⁵ and R⁶.

Another preferred embodiment of this invention is described by formulaI, wherein R² denotes phenyl, naphthyl, pyrrolyl, furanyl, thienyl,pyridinyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl,isoquinolinyl, or

-   -   pyrrolyl, furanyl, thienyl, pyridinyl wherein 1 or 2 CH are        replaced by N, or    -   indolyl, benzofuranyl, benzothiophenyl, quinolinyl,        isoquinolinyl, wherein 1 or 2 CH are replaced by N,    -   while the above-mentioned aromatic and heteroaromatic rings are        optionally substituted with one to four R⁷.

Another preferred embodiment of this invention is described by formulaI, wherein R² denotes phenyl, naphthyl, furanyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, indoly, benzimidazolyl, benzoxazolyl,quinolinyl, or isoquinolinyl, wherein each of these groups is optionallysubstituted with one, two, or three R⁷.

Another preferred embodiment of this invention is described by formulaI, wherein R² denotes phenyl, naphthyl, or pyridinyl that are optionallysubstituted with one, two, or three R⁷.

Another preferred embodiment of this invention is described by formulaI, wherein R² denotes phenyl optionally substituted with one or two R⁷.

Another preferred embodiment of this invention is described by formulaI, wherein R⁴ denotes

-   -   fluorine, chlorine, bromine, C₁₋₄-alkyl, hydroxy, C₁₋₄-alkyloxy,    -   nitro, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino,        pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, piperidin-1-yl,        2-oxo-piperidin-1-yl, morpholin-4-yl, 3-oxo-morpholin-4-yl,        piperazin-1-yl, 2-oxo-piperazin-1-yl, 3-oxo-piperazin-1-yl,        4-(C₁₋₃-alkyl)piperazin-1-yl,        4-(C₁₋₄-alkylcarbonyl)-piperazin-1-yl,        4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkyloxycarbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl,        2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,        3-oxo-4-(C₁₋₃-alkyl)piperazin-1-yl,    -   C₁₋₃-alkyl-carbonylamino, (het)arylcarbonylamino,        (het)aryl-C₁₋₃-alkyl-carbonylamino, C₁₋₃-alkyloxy-carbonylamino,        aminocarbonylamino, C₁₋₃-alkyl-aminocarbonylamino,        di-(C₁₋₃-alkyl)aminocarbonylamino,        pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamino,        morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino,        4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonylamino,        C₁₋₃-alkyl-sulfonylamino, (het)arylsulfonylamino,        (het)aryl-C₁₋₃-alkyl-sulfonylamino,    -   N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-carbonylamino,        N—(C₁₋₃-alkyl)-(het)arylcarbonylamino,        N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkyl-carbonylamino,        N—(C₁₋₃-alkyl)-C₁₋₃-alkyloxy-carbonylamino,        N-(aminocarbonyl)-C₁₋₃-alkylamino,        N—(C₁₋₃-alkyl-aminocarbonyl)-C₁₋₃-alkylamino,        N-[di-(C₁₋₃-alkyl)aminocarbonyl]-C₁₋₃-alkylamino,    -   N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-sulfonylamino,        N—(C₁₋₃-alkyl)-(het)arylsulfonylamino,        N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkyl-sulfonylamino,        oxo-imidazolidinyl, 2,4-dioxo-imidazolidinyl,        2,5-dioxo-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl,        wherein the nitrogen atom in position 3 of the aforementioned        groups is optionally substituted with methyl,    -   1,1-dioxo-[1,2]thiazinan-2-yl,    -   cyano, carboxy, C₁₋₃-alkyloxy-carbonyl, aminocarbonyl,        C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,        pyrrolidin-1-yl-carbonyl,    -   2-(methoxymethyl)-pyrrolidin-1-yl-carbonyl,        3-(methoxymethyl)-pyrrolidin-1-yl-carbonyl,        piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl,        piperazin-1-yl-carbonyl, 4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl,        (het)arylaminocarbonyl, N—(C₁₋₃-alkyl)-(het)arylaminocarbonyl,        (het)aryl-C₁₋₃-alkylaminocarbonyl,        N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkylaminocarbonyl,    -   C₁₋₄-alkyl-carbonyl, (het)aryl-carbonyl,    -   C₁₋₃-alkylcarbonyl-C₁₋₃-alkyl, carboxy-C₁₋₃-alkyl,        C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyl, cyano-C₁₋₃-alkyl,        aminocarbonyl-C₁₋₃-alkyl, C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyl,        di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl,        pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl,        piperidin-1-yl-carbonyl-C₁₋₃-alkyl,        morpholin-4-yl-carbonyl-C₁₋₃-alkyl,        piperazin-1-yl-carbonyl-C₁₋₃-alkyl,        4-(C₁₋₃-alkyl)piperazin-1-yl-carbonyl-C₁₋₃-alkyl,    -   carboxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyloxy,        cyano-C₁₋₃-alkyloxy, aminocarbonyl-C₁₋₃-alkyloxy,        C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyloxy,        di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy,        pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl-oxy,        piperidin-1-yl-carbonyl-C₁₋₃-alkyloxy,        morpholin-4-yl-carbonyl-C₁₋₃-alkyl-oxy,        piperazin-1-yl-carbonyl-C₁₋₃-alkyloxy,        4-(C₁₋₃-alkyl)piperazin-1-yl-carbonyl-C₁₋₃-alkyloxy,    -   hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl,        C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,        pyrrolidin-1-yl-C₁₋₃-alkyl, 2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl,        piperidin-1-yl-C₁₋₃-alkyl, 2-oxo-piperidin-1-yl-C₁₋₃-alkyl,        morpholin-4-yl-C₁₋₃-alkyl, (methyl-morpholin-4-yl)-C₁₋₃-alkyl,        (dimethyl-morpholin-4-yl)-C₁₋₃-alkyl,        3-oxo-morpholin-4-yl-C₁₋₃-alkyl, piperazin-1-yl-C₁₋₃-alkyl,        2-oxo-piperazin-1-yl-C₁₋₃-alkyl,        3-oxo-piperazin-1-yl-C₁₋₃-alkyl,        4-(C₁₋₃-alkyl)piperazin-1-yl-C₁₋₃-alkyl,        2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,        3-oxo-4-(C₁₋₃-alkyl)piperazin-1-yl-C₁₋₃-alkyl,    -   C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl,        (het)arylcarbonylamino-C₁₋₃-alkyl,    -   hydroxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-C₁₋₃-alkyloxy,        C₁₋₃-alkylsulfanyl-C₁₋₃-alkyloxy,        C₁₋₃-alkylsulfinyl-C₁₋₃-alkyloxy,        C₁₋₃-alkylsulfonyl-C₁₋₃-alkyloxy, amino-C₁₋₃-alkyloxy,        C₁₋₃-alkylamino-C₁₋₃-alkyloxy,        di-(C₁₋₃-alkyl)amino-C₁₋₃-alkyloxy,        pyrrolidin-1-yl-C₁₋₃-alkyloxy,        2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyloxy,        piperidin-1-yl-C₁₋₃-alkyloxy,        2-oxo-piperidin-1-yl-C₁₋₃-alkyloxy,        morpholin-4-yl-C₁₋₃-alkyloxy,        3-oxo-morpholin-4-yl-C₁₋₃-alkyloxy,        piperazin-1-yl-C₁₋₃-alkyloxy,        2-oxo-piperazin-1-yl-C₁₋₃-alkyloxy,        3-oxo-piperazin-1-yl-C₁₋₃-alkyloxy,        4-(C₁₋₃-alkyl)piperazin-1-yl-C₁₋₃-alkyloxy,        2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyloxy,        3-oxo-4-(C₁₋₃-alkyl)piperazin-1-yl-C₁₋₃-alkyloxy,    -   C₁₋₃-alkylsulfanyl, C₁₋₃-alkysulfinyl, C₁₋₃-alkylsulfonyl,        (het)arylsulfonyl,    -   aminosulfonyl, C₁₋₃-alkyl-aminosulfonyl,        di-(C₁₋₃-alkyl)-aminosulfonyl, pyrrolidin-1-yl-sulfonyl,        piperidin-1-yl-sulfonyl, morpholin-4-yl-sulfonyl,        piperazin-1-yl-sulfonyl, 4-(C₁₋₃-alkyl)piperazin-1-yl-sulfonyl,    -   difluoromethyl, trifluoromethyl, difluoromethoxy,        trifluoromethoxy,    -   2,2,2-trifluoro-1-hydroxyethyl,        2,2,2-trifluoro-1-hydroxy-1-methylethyl,        2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl,    -   C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyloxy,    -   C₃₋₆-cycloalkyl-C₁₋₃-alkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyloxy,    -   (het)aryl, (het)aryloxy, (het)aryl-C₁₋₃-alkyl,        (het)aryl-C₁₋₃-alkyloxy, (het)aryloxy-C₁₋₃-alkyl, or    -   tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,        tetrahydropyran-4-yloxy, tetrahydro-furanyl-C₁₋₃-alkyloxy,        tetrahydropyranyl-C₁₋₃-alkyloxy, thietan-3-yloxy,    -   wherein the above-mentioned (het)aryl groups are phenyl,        naphthyl, or    -   pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl,        benzothiophenyl, quinolinyl, isoquinolinyl, or    -   pyrrolyl, furanyl, thienyl, imidazolyl, pyridyl wherein 1 or 2        CH are replaced by N, or indolyl, benzofuranyl, benzothiophenyl,        quinolinyl, isoquinolinyl wherein 1 to 3 CH are replaced by N,        or    -   1,2-dihydro-2-oxo-pyridinyl, 1,4-dihydro-4-oxo-pyridinyl,        2,3-dihydro-3-oxo-pyridazinyl,        1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl,        1,2-dihydro-2-oxo-pyrimidinyl, 3,4-dihydro-4-oxo-pyrimidinyl,        1,2,3,4-tetrahydro-2,4-dioxo-pyrimidinyl,        1,2-dihydro-2-oxo-pyrazinyl,        1,2,3,4-tetrahydro-2,3-dioxo-pyrazinyl,        2,3-dihydro-2-oxo-indolyl, 2,3-dihydrobenzofuranyl,        2,3-dihydro-2-oxo-1H-benzimidazolyl,        2,3-dihydro-2-oxo-benzoxazolyl, 1,2-dihydro-2-oxo-quinolinyl,        1,4-dihydro-4-oxo-quinolinyl, 1,2-dihydro-1-oxo-isoquinolinyl,        1,4-dihydro-4-oxo-cinnolinyl, 1,2-dihydro-2-oxo-quinazolinyl,        1,4-dihydro-4-oxo-quinazolinyl,        1,2,3,4-tetrahydro-2,4-dioxo-quinazolinyl,        1,2-dihydro-2-oxoquinoxalinyl,        1,2,3,4-tetrahydro-3-oxo-quinoxalinyl,        1,2,3,4-tetrahydro-2,3-dioxo-quinoxalinyl,        1,2-dihydro-1-oxo-phthalazinyl,        1,2,3,4-tetrahydro-1,4-dioxo-phthalazinyl, chromanyl,        coumarinyl, 2,3-dihydro-benzo[1,4]dioxinyl,        3,4-dihydro-3-oxo-2H-benzo[1,4]oxazinyl, and    -   wherein all the above-mentioned (het)aryl groups are optionally        substituted with 1, 2 or 3 R¹¹ which may be identical or        different.

Another preferred embodiment of this invention is described by formulaI, wherein R⁴ denotes

-   -   fluorine, chlorine, bromine, C₁₋₄-alkyl, hydroxy, C₁₋₄-alkyloxy,        thietan-3-yloxy,    -   amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino, pyrrolidin-1-yl,        2-oxo-pyrrolidin-1-yl, piperidin-1-yl, 2-oxo-piperidin-1-yl,        morpholin-4-yl, 3-oxo-morpholin-4-yl, piperazin-1-yl,        2-oxo-piperazin-1-yl, 3-oxo-piperazin-1-yl,        4-(C₁₋₃-alkyl)piperazin-1-yl,        4-(C₁₋₄-alkylcarbonyl)-piperazin-1-yl,        4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkyloxycarbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl,        2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,        3-oxo-4-(C₁₋₃-alkyl)piperazin-1-yl,    -   C₁₋₃-alkyl-carbonylamino, (het)arylcarbonylamino,        (het)aryl-C₁₋₃-alkyl-carbonylamino, C₁₋₃-alkyloxy-carbonylamino,        aminocarbonylamino, C₁₋₃-alkyl-aminocarbonylamino,        di-(C₁₋₃-alkyl)aminocarbonylamino,        pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamino,        morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino,        4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonylamino,    -   2-oxo-imidazolidinyl, 1,1-dioxo-[1,2]thiazinanyl,    -   cyano, carboxy, C₁₋₃-alkyloxy-carbonyl, aminocarbonyl,        C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,        pyrrolidin-1-yl-carbonyl,        2-(methoxymethyl)-pyrrolidin-1-yl-carbonyl,        3-(methoxymethyl)-pyrrolidin-1-yl-carbonyl,        piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl,        piperazin-1-yl-carbonyl, 4-(C₁₋₃-alkyl)piperazin-1-yl-carbonyl,        N—(C₁₋₃-alkyl)-(het)arylaminocarbonyl,        N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkylaminocarbonyl,    -   C₁₋₄-alkyl-carbonyl, (het)aryl-carbonyl,    -   C₁₋₃-alkylcarbonyl-C₁₋₃-alkyl, hydroxy-C₁₋₃-alkyl,        C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl,        C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,        pyrrolidin-1-yl-C₁₋₃-alkyl, 2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl,        morpholin-4-yl-C₁₋₃-alkyl,    -   C₁₋₃-alkylsulfonyl, aminosulfonyl,    -   C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl,        (het)arylcarbonylamino-C₁₋₃-alkyl,    -   hydroxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-C₁₋₃-alkyloxy,    -   difluoromethyl, trifluoromethyl, difluoromethoxy,        trifluoromethoxy,    -   2,2,2-trifluoro-1-hydroxyethyl,        2,2,2-trifluoro-1-hydroxy-1-methylethyl,        2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl,    -   (het)aryl, (het)aryl-C₁₋₃-alkyl, or (het)aryloxy,    -   wherein the above-mentioned (het)aryl groups are phenyl,        naphthyl, pyrrolyl, furanyl, thienyl, pyridyl, indolyl,        benzofuranyl, benzothiophenyl, quinolinyl, and isoquinolinyl, or    -   pyrrolyl, furanyl, thienyl, imidazolyl, or pyridyl wherein 1 or        2 CH are replaced by N, or    -   indolyl, benzofuranyl, benzothiophenyl, quinolinyl, or        isoquinolinyl wherein 1 to 3 CH are replaced by N, and    -   wherein the above-mentioned (het)aryl groups are optionally        substituted with 1, 2, or 3 R¹¹ which may be identical or        different.

Another preferred embodiment of this invention is described by formulaI, wherein R⁴ denotes fluorine, chlorine, C₁₋₄-alkyl, difluoromethyl,trifluoromethyl, hydroxy, C₁₋₄-alkyloxy, difluoromethoxy,trifluoromethoxy, thietan-3-yloxy, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl,C₁₋₃-alkyl-carbonylamino, C₁₋₄-alkylcarbonyl, carboxy, cyano,C₁₋₃-alkoxycarbonyl, amino-carbonyl, C₁₋₃-alkyl-amino-carbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, 2-oxo-pyrrolidin-1-yl,hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,morpholin-4-yl-C₁₋₃-alkyl, C₁₋₃-alkylcarbonyl-C₁₋₃-alkyl,C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl, 1,1-dioxo-[1,2]thiazinan-2-yl,2-oxo-imidazolidinyl, C₁₋₃alkylsulfonyl, aminosulfonyl, phenyl,pyrazolyl, oxazolyl, [1,2,4]oxadiazol-3-yl, or tetrazol-1-yl, while thearomatic and heteroaromatic groups listed are optionally substitutedwith 1, 2, or 3 groups R¹¹ which may be identical or different.

Another preferred embodiment of this invention is described by formulaI, wherein R⁴ denotes fluorine, chlorine, methyl, ethyl, iso-butyl,tert-butyl, difluoromethyl, trifluoromethyl, hydroxy, methoxy,tert-butyloxy, thietan-3-yloxy, amino, methylamino, acetylamino,hydroxymethyl, acetylaminomethyl, carboxy, cyano, methoxycarbonyl,aminocarbonyl, methylaminocarbonyl, 2-oxo-pyrrolidin-1-yl,methylcarbonyl, 2-oxo-imidazolidinyl, methylsulfonyl, aminosulfonyl,phenyl, pyrazol-3-yl, oxazol-5-yl, 5-methyl-[1,2,4]oxadiazol-3-yl,tetrazol-1-yl, or tetrazol-5-yl.

Another preferred embodiment of this invention is described by formulaI, wherein R⁷ denotes

-   -   halogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, hydroxy,        C₁₋₄-alkyloxy, nitro, amino, C₁₋₃-alkylamino,        di-(C₁₋₃-alkyl)amino, pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl,        piperidin-1-yl, 2-oxo-piperidin-1-yl, morpholin-4-yl,        3-oxo-morpholin-4-yl, piperazin-1-yl, 2-oxo-piperazin-1-yl,        3-oxo-piperazin-1-yl, 4-(C₁₋₄-alkylcarbonyl)piperazin-1-yl,        4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkyloxycarbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl,        2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,        3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,    -   C₁₋₃alkyl-carbonylamino, (het)aryl-carbonylamino,        C₁₋₃alkyloxy-carbonylamino, aminocarbonylamino,        C₁₋₃-alkyl-aminocarbonylamino,        di-(C₁₋₃-alkyl)amino-carbonylamino,        pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamino,        morpholin-4-yl-carbonylamino, C₁₋₃-alkyl-sulfonylamino,        C₁₋₃-alkylamino-sulfonylamino,        di-(C₁₋₃alkyl)amino-sulfonylamino,        pyrrolidin-1-yl-sulfonylamino, piperidin-1-yl-sulfonylamino,        morpholin-4-yl-sulfonylamino, (het)arylsulfonylamino,    -   N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-carbonylamino,        N—(C₁₋₃-alkyl)-(het)arylcarbonylamino,        N—(C₁₋₃-alkyl)-C₁₋₃-alkyloxy-carbonylamino,        N-(aminocarbonyl)-C₁₋₃-alkylamino,        N—(C₁₋₃-alkyl-aminocarbonyl)-C₁₋₃-alkylamino,        N-[di-(C₁₋₃-alkyl)aminocarbonyl]-C₁₋₃-alkylamino,    -   N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-sulfonylamino,        N—(C₁₋₃-alkyl)-(het)arylsulfonylamino,    -   cyano, carboxy, C₁₋₃-alkyloxy-carbonyl, aminocarbonyl,        C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,        pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,        morpholin-4-yl-carbonyl, piperazin-1-yl-carbonyl,        4-(C₁₋₃-alkyl)piperazin-1-yl-carbonyl, (het)arylaminocarbonyl,        N—(C₁₋₃-alkyl)-(het)arylaminocarbonyl,        (het)aryl-C₁₋₃-alkyl-aminocarbonyl,        N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkylaminocarbonyl,    -   C₁₋₄-alkyl-carbonyl, (het)aryl-carbonyl,    -   carboxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyl,        cyano-C₁₋₃-alkyl, aminocarbonyl-C₁₋₃-alkyl,        C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyl,        di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl,        pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl,        piperidin-1-yl-carbonyl-C₁₋₃-alkyl,        morpholin-4-yl-carbonyl-C₁₋₃-alkyl,    -   carboxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyloxy,        cyano-C₁₋₃-alkyloxy, aminocarbonyl-C₁₋₃-alkyloxy,        C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyloxy,        di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy,        pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl-oxy,        piperidin-1-yl-carbonyl-C₁₋₃-alkyloxy,        morpholin-4-yl-carbonyl-C₁₋₃-alkyl-oxy,    -   hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl,        C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,        pyrrolidin-1-yl-C₁₋₃-alkyl, 2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl,        piperidin-1-yl-C₁₋₃-alkyl, 2-oxo-piperidin-1-yl-C₁₋₃-alkyl,        morpholin-4-yl-C₁₋₃-alkyl, 3-oxo-morpholin-4-yl-C₁₋₃-alkyl,        3-oxo-piperazin-1-yl-C₁₋₃-alkyl,        3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,    -   C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl,        arylcarbonylamino-C₁₋₃-alkyl,    -   hydroxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-C₁₋₃-alkyloxy,        C₁₋₃-alkylsulfanyl-C₁₋₃-alkyloxy,        C₁₋₃-alkylsulfinyl-C₁₋₃-alkyloxy,        C₁₋₃-alkylsulfonyl-C₁₋₃-alkyloxy, amino-C₁₋₃-alkyloxy,        C₁₋₃-alkylamino-C₁₋₃-alkyloxy,        di-(C₁₋₃-alkyl)amino-C₁₋₃-alkyloxy,        pyrrolidin-1-yl-C₁₋₃-alkyloxy,        2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyloxy,        piperidin-1-yl-C₁₋₃-alkyloxy,        2-oxo-piperidin-1-yl-C₁₋₃-alkyloxy,        morpholin-4-yl-C₁₋₃-alkyloxy,        3-oxo-morpholin-4-yl-C₁₋₃-alkyloxy,        3-oxo-piperazin-1-yl-C₁₋₃-alkyloxy,        3-oxo-4-(C₁₋₃-alkyl)piperazin-1-yl-C₁₋₃-alkyloxy,    -   C₁₋₃-alkylsulfanyl, C₁₋₃-alkysulfinyl, C₁₋₃-alkylsulfonyl,        (het)arylsulfonyl, trifluoromethylsulfinyl,        trifluoromethylsulfonyl,    -   aminosulfonyl, C₁₋₃-alkyl-aminosulfonyl,        di-(C₁₋₃-alkyl)-aminosulfonyl, pyrrolidin-1-yl-sulfonyl,        piperidin-1-yl-sulfonyl, morpholin-4-yl-sulfonyl,    -   difluoromethyl, trifluoromethyl, difluoromethoxy,        trifluoromethoxy,    -   C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyloxy,    -   C₃₋₆-cycloalkyl-C₁₋₃-alkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyloxy,    -   (het)aryl, (het)aryloxy, (het)aryl-C₁₋₃-alkyl,        (het)aryl-C₁₋₃-alkyloxy, (het)aryloxy-C₁₋₃-alkyl, or    -   tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,        tetrahydropyran-4-yloxy, tetrahydrofuranyl-C₁₋₃-alkyloxy,        tetrahydropyranyl-C₁₋₃-alkyloxy,    -   wherein the above-mentioned (het)aryl is phenyl, naphthyl,        pyrrolyl, furanyl, thienyl, pyridyl, or    -   pyrrolyl, furanyl, thienyl, imidazolyl, pyridyl in which 1 or 2        CH are replaced by N, and wherein the above-mentioned (het)aryl        groups are optionally substituted with one or two R¹¹ which may        be identical or different.

Another preferred embodiment of this invention is described by formulaI, wherein R⁷ denotes

-   -   denotes fluorine, chlorine, bromine,    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, hydroxy, C₁₋₄-alkyloxy,        amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino,    -   C₁₋₃-alkyl-carbonylamino, C₁₋₃-alkyloxy-carbonylamino,        aminocarbonylamino, C₁₋₃-alkyl-aminocarbonylamino,        di-(C₁₋₃-alkyl)aminocarbonylamino, C₁₋₃-alkyl-sulfonylamino,    -   N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-carbonylamino,        N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-sulfonylamino, cyano, carboxy,        C₁₋₃-alkyloxy-carbonyl, aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl,        di-(C₁₋₃-alkyl)-aminocarbonyl, pyrrolidin-1-yl-carbonyl,        piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl,    -   carboxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyl,        cyano-C₁₋₃-alkyl, aminocarbonyl-C₁₋₃-alkyl,        C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyl,        di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl,    -   carboxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyloxy,        cyano-C₁₋₃-alkyloxy,    -   hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl,        C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,    -   C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl,    -   hydroxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-C₁₋₃-alkyloxy,    -   C₁₋₃-alkylsulfonyl, trifluoromethylsulfonyl,    -   aminosulfonyl, C₁₋₃-alkyl-aminosulfonyl,        di-(C₁₋₃-alkyl)-aminosulfonyl,    -   difluoromethyl, trifluoromethyl, difluoromethoxy,        trifluoromethoxy,    -   C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyloxy,    -   tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,        tetrahydropyran-4-yloxy, tetrahydrofuranyl-C₁₋₃-alkyloxy,        tetrahydropyranyl-C₁₋₃-alkyloxy, or    -   phenyl or phenoxy that are optionally substituted with one or        two identical or different R¹¹.

Another preferred embodiment of this invention is described by formulaI, wherein R⁷ denotes fluorine, chlorine, bromine, C₁₋₄-alkyl,trifluoromethyl, hydroxy, C₁₋₄-alkyloxy, trifluoromethoxy, phenoxy,amino-C₁₋₃-alkyl, carboxy, cyano, C₁₋₃-alkoxycarbonyl, aminocarbonyl,C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl, or phenyl.

Another preferred embodiment of this invention is described by formulaI, wherein R⁷ denotes fluorine, chlorine, bromine, methyl, isopropyl,trifluoromethyl, hydroxy, methoxy, trifluoromethoxy, phenoxy,aminomethyl, carboxy, methoxycarbonyl, aminocarbonyl, or phenyl.

The compounds of general formula I according to the invention and thephysiologically acceptable salts thereof have valuable pharmacologicalproperties, particularly an inhibitory effect on the enzyme11β-hydroxysteroid dehydrogenase (HSD) 1.

The first aspect of the invention also relates to the physiologicallyacceptable salts of the compounds of general formula I with inorganic ororganic acids.

In a second aspect this invention relates to pharmaceuticalcompositions, containing at least one compound of general formula I or aphysiologically acceptable salt according to the invention, optionallytogether with one or more inert carriers and/or diluents.

In a third aspect this invention relates to the compounds according togeneral formula I or the physiologically acceptable salts thereof fortreatment or prevention of diseases or conditions which can beinfluenced by inhibiting the enzyme 11β-hydroxysteroid dehydrogenase(HSD) 1, such as metabolic disorders.

In a fourth aspect this invention relates to the use of at least onecompound according to general formula I or one of the physiologicallyacceptable salts thereof for preparing a pharmaceutical compositionwhich is suitable for the treatment or prevention of diseases orconditions which can be influenced by inhibiting the enzyme11β-hydroxysteroid dehydrogenase (HSD) 1, such as metabolic disorders.

In a fifth aspect the invention relates to a process for preparing apharmaceutical composition according to the invention, characterized inthat a compound of general formula I or one of the physiologicallyacceptable salts thereof is incorporated in one or more inert carriersand/or diluents by a non-chemical method.

In a sixth aspect the present invention relates to a process forpreparing the compounds of general formula I, characterized in that

in order to prepare compounds of general formula I which are defined ashereinbefore and hereinafter,a compound of general formula II

wherein the group R² is defined as hereinbefore and hereinafter;is reacted with a compound of general formula R¹—CO—Y, optionallyprepared in situ from the corresponding carboxylic acid,wherein R¹ is defined as hereinbefore and hereinafter andY is a leaving group and in particular denotes

-   -   fluorine, chlorine, bromine, cyano, C₁₋₄-alkoxy,        C₂₋₄-alkenyloxy, C₂₋₄-alkynyloxy, C₁₋₄-alkylsulfanyl,        arylotriazoloxy, heteroarylotriazoloxy, heteroaryl,        succinyl-N-oxy, C₁₋₄-alkylcarbonyloxy,        di-(C₁₋₄-alkyl)aminocarbonyloxy, pyrrolylcarbonyloxy,        piperidinyl-carbonyloxy, morpholinylcarbonyloxy,        tri-(C₁₋₄-alkyl)-carbamimidoyloxy,        N,N,N′,N′-tetra-(C₁₋₄-alkyl)uronyl, N,N′-dicyclohexyluronyl,        di-(C₁₋₄-alkyloxy)-phosphoryloxy,        di-(di-C₁₋₄-alkylamino)-phosphoryloxy,        dipyrrolidinylphosphoryloxy, aryloxy, arylsulfanyl,        heterosulfanyl, or heteroaryloxy,    -   while the alkyl, alkenyl, and alkynyl groups mentioned in the        definition of the above groups optionally are mono- or        polysubstituted with fluorine, chlorine, C₁₋₃-alkyl, or        C₁₋₃-alkoxy,    -   while the aryl groups mentioned in the definition of the above        groups, either alone or as part of another group, denote phenyl        or naphthyl groups and the heteroaryl groups mentioned in the        definition of the above groups, either alone or as part of        another group, denote pyridinyl, pyrimidinyl, triazinyl,        imidazolyl, pyrazolyl, triazolyl, tetrazolyl, whilst both the        aryl and heteroaryl groups optionally are independently mono- or        polysubstituted with fluorine, chlorine, bromine, C₁₋₃-alkyl,        C₁₋₃-alkyloxy, nitro, cyano, or di-(C₁₋₃-alkyl)amino groups,        optionally in the presence of a base or another additive;        and if necessary any protective group used in the reactions        described above is cleaved concurrently or subsequently;        if desired a compound of general formula I thus obtained is        resolved into its stereoisomers;        if desired a compound of general formula I thus obtained is        converted into the salts thereof, particularly for        pharmaceutical use into the physiologically acceptable salts        thereof.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise stated, the groups, residues, and substituents,particularly R¹, R², R⁴, R⁵, R⁶, R⁷, and R¹¹ are defined as above andhereinafter. If residues, substituents, or groups occur several times ina compound they may have the same or different meanings. Some preferredmeanings of groups and substituents of the compounds according to theinvention will be given hereinafter.

Preferred embodiments of the invention are characterized by thefollowing definitions:

a) Definitions (a^(i)) for R¹ in the order of preference, ascending frompreferably (a¹) to more preferably (a²) up to most preferably (a⁴):(a¹): Preferably, R¹ denotes phenyl, naphthyl, pyrrolyl, furanyl,thienyl, pyridinyl, indolyl,

-   -   benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, or    -   pyrrolyl, furanyl, thienyl, pyridinyl wherein 1 or 2 CH are        replaced by N, or    -   indolyl, benzofuranyl, benzothiophenyl, quinolinyl,        isoquinolinyl, wherein 1 or 2 CH are replaced by N, or    -   indolinyl, 2-oxo-2,3-dihydro-indolyl,        1-oxo-2,3-dihydro-isoindolyl, 2-oxo-2,3-dihydro-benzoimidazolyl,        pyrazolo[1,5-a]pyrimidinyl,        7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidinyl,        [1,2,4]triazolo[1,5-a]pyrimidinyl,        4-oxo-3,4-dihydro-quinazolinyl, tetrahydroquinolinyl,    -   wherein the above-mentioned aromatic and heteroaromatic groups        are optionally substituted with one or more, preferably one to        four, substituents R⁴ and wherein 2 adjacent C-atoms are        optionally substituted with R⁵ and R⁶.        (a²): More preferably, R¹ denotes phenyl, naphthyl, furanyl,        thienyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolyl,        [1,2,5]-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,        pyridazinyl, benzofuranyl, indolyl, indolinyl,        2-oxo-2,3-dihydro-indolyl, 1-oxo-2,3-dihydro-isoindolyl,        indazolyl, benzimidazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl,        benzoxazolyl, benzotriazolyl, benzothiazolyl,        pyrazolo[1,5-a]pyrimidinyl,        7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidinyl, quinoxalinyl,        quinolinyl, isoquinolinyl, quinazolinyl,        4-oxo-3,4-dihydro-quinazolinyl, naphthyridinyl, and        1,2,3,4-tetrahydroquinolinyl, each of these groups is optionally        substituted with one or more, preferably one to four,        substituents R⁴ and/or at 2 adjacent C-atoms with R⁵ and R⁶.        (a³): Even more preferably, R¹ denotes phenyl, furanyl, thienyl,        pyrazolyl, thiazolyl, pyridinyl, benzofuranyl, indolyl,        indolinyl, 2-oxo-2,3-dihydro-1H-indolyl,        1-oxo-2,3-dihydro-1H-isoindolyl, indazolyl, benzimidazolyl,        2-oxo-2,3-dihydro-1H-benzoimidazolyl, benzotriazolyl,        benzothiazolyl, quinoxalinyl, quinolinyl, isoquinolinyl,        4-oxo-3,4-dihydro-quinazolinyl, and        1,2,3,4-tetrahydroquinolinyl, each of these groups is optionally        substituted with one to four substituents R⁴ and/or at 2        adjacent C-atoms with R⁵ and R⁶.        (a⁴): Most preferably, R¹ denotes phenyl, benzofuranyl, indolyl,        2-oxo-2,3-dihydro-1H-indolyl, indazolyl, benzimidazolyl,        benzotriazolyl, benzothiazolyl, quinoxalinyl, quinolinyl, and        1,2,3,4-tetrahydroquinolinyl, each of these groups is optionally        substituted with one, two, or three substituents R⁴ or        optionally substituted with one or two substituents R⁴ and/or at        2 adjacent C-atoms with R⁵ and R⁶.        b) Definitions (b^(i)) for R² in the order of preference,        ascending from preferably (b¹) to more preferably (b²) up to        most preferably (b⁴):        (b¹): Preferably, R² denotes phenyl, naphthyl, pyrrolyl,        furanyl, thienyl, pyridinyl, indolyl, benzofuranyl,        benzothiophenyl, quinolinyl, isoquinolinyl, or    -   pyrrolyl, furanyl, thienyl, pyridinyl wherein 1 or 2 CH are        replaced by N, or    -   indolyl, benzofuranyl, benzothiophenyl, quinolinyl,        isoquinolinyl, wherein 1 or 2 CH are replaced by N,    -   while the above-mentioned aromatic and heteroaromatic rings are        optionally substituted with one to four R⁷.        (b²): More preferably, R² denotes phenyl, naphthyl, furanyl,        pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indoly,        benzimidazolyl, benzoxazolyl, quinolinyl, or isoquinolinyl, each        of these groups is optionally substituted with one, two, or        three R⁷.        (b³): Even more preferably, R² denotes phenyl, naphthyl, or        pyridinyl that are optionally substituted with one, two, or        three R⁷.        (b⁴): Most preferably, R² denotes phenyl optionally substituted        with one or two R⁷.        c) Definitions (c^(i)) for R⁴ in the order of preference,        ascending from preferably (c¹) to more preferably (c²) up to        most preferably (c⁴):        (c¹): Preferably, R⁴ denotes fluorine, chlorine, bromine,        C₁₋₄-alkyl, hydroxy, C₁₋₄-alkyloxy,    -   nitro, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino,        pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, piperidin-1-yl,        2-oxo-piperidin-1-yl, morpholin-4-yl, 3-oxo-morpholin-4-yl,        piperazin-1-yl, 2-oxo-piperazin-1-yl, 3-oxo-piperazin-1-yl,        4-(C₁₋₃-alkyl)piperazin-1-yl,        4-(C₁₋₄-alkylcarbonyl)-piperazin-1-yl,        4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkyloxycarbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl,        2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,        3-oxo-4-(C₁₋₃-alkyl)piperazin-1-yl,    -   C₁₋₃-alkyl-carbonylamino, (het)arylcarbonylamino,        (het)aryl-C₁₋₃-alkyl-carbonylamino, C₁₋₃-alkyloxy-carbonylamino,        aminocarbonylamino, C₁₋₃-alkyl-aminocarbonylamino,        di-(C₁₋₃-alkyl)aminocarbonylamino,        pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamino,        morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino,        4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonylamino,        C₁₋₃-alkyl-sulfonylamino, (het)arylsulfonylamino,        (het)aryl-C₁₋₃-alkyl-sulfonylamino,    -   N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-carbonylamino,        N—(C₁₋₃-alkyl)-(het)arylcarbonylamino,        N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkyl-carbonylamino,        N—(C₁₋₃-alkyl)-C₁₋₃-alkyloxy-carbonylamino,        N-(aminocarbonyl)-C₁₋₃-alkylamino,        N—(C₁₋₃-alkyl-aminocarbonyl)-C₁₋₃-alkylamino,        N-[di-(C₁₋₃-alkyl)aminocarbonyl]-C₁₋₃-alkylamino,    -   N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-sulfonylamino,        N—(C₁₋₃-alkyl)-(het)arylsulfonylamino,        N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkyl-sulfonylamino,    -   oxo-imidazolidinyl, 2,4-dioxo-imidazolidinyl,        2,5-dioxo-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl,        wherein the nitrogen atom in position 3 of the aforementioned        groups is optionally substituted with methyl,    -   1,1-dioxo-[1,2]thiazinan-2-yl,    -   cyano, carboxy, C₁₋₃-alkyloxy-carbonyl, aminocarbonyl,        C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,        pyrrolidin-1-yl-carbonyl,    -   2-(methoxymethyl)-pyrrolidin-1-yl-carbonyl,        3-(methoxymethyl)-pyrrolidin-1-yl-carbonyl,        piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl,        piperazin-1-yl-carbonyl, 4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl,        (het)arylaminocarbonyl, N—(C₁₋₃-alkyl)-(het)arylaminocarbonyl,        (het)aryl-C₁₋₃-alkylaminocarbonyl,        N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkylaminocarbonyl,    -   C₁₋₄-alkyl-carbonyl, (het)aryl-carbonyl,    -   C₁₋₃-alkylcarbonyl-C₁₋₃-alkyl, carboxy-C₁₋₃-alkyl,        C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyl, cyano-C₁₋₃-alkyl,        aminocarbonyl-C₁₋₃-alkyl, C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyl,        di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl,        pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl,        piperidin-1-yl-carbonyl-C₁₋₃-alkyl,        morpholin-4-yl-carbonyl-C₁₋₃-alkyl,        piperazin-1-yl-carbonyl-C₁₋₃-alkyl,        4-(C₁₋₃-alkyl)piperazin-1-yl-carbonyl-C₁₋₃-alkyl,    -   carboxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyloxy,        cyano-C₁₋₃-alkyloxy, aminocarbonyl-C₁₋₃-alkyloxy,        C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyloxy,        di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy,        pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl-oxy,        piperidin-1-yl-carbonyl-C₁₋₃-alkyloxy,        morpholin-4-yl-carbonyl-C₁₋₃-alkyl-oxy,        piperazin-1-yl-carbonyl-C₁₋₃-alkyloxy,        4-(C₁₋₃-alkyl)piperazin-1-yl-carbonyl-C₁₋₃-alkyloxy,    -   hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl,        C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,        pyrrolidin-1-yl-C₁₋₃-alkyl, 2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl,        piperidin-1-yl-C₁₋₃-alkyl, 2-oxo-piperidin-1-yl-C₁₋₃-alkyl,        morpholin-4-yl-C₁₋₃-alkyl, (methyl-morpholin-4-yl)-C₁₋₃-alkyl,        (dimethyl-morpholin-4-yl)-C₁₋₃-alkyl,        3-oxo-morpholin-4-yl-C₁₋₃-alkyl, piperazin-1-yl-C₁₋₃-alkyl,        2-oxo-piperazin-1-yl-C₁₋₃-alkyl,        3-oxo-piperazin-1-yl-C₁₋₃-alkyl,        4-(C₁₋₃-alkyl)piperazin-1-yl-C₁₋₃-alkyl,        2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,        3-oxo-4-(C₁₋₃-alkyl)piperazin-1-yl-C₁₋₃-alkyl,    -   C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl,        (het)arylcarbonylamino-C₁₋₃-alkyl,    -   hydroxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-C₁₋₃-alkyloxy,        C₁₋₃-alkylsulfanyl-C₁₋₃-alkyloxy,        C₁₋₃-alkylsulfinyl-C₁₋₃-alkyloxy,        C₁₋₃-alkylsulfonyl-C₁₋₃-alkyloxy, amino-C₁₋₃-alkyloxy,        C₁₋₃-alkylamino-C₁₋₃-alkyloxy,        di-(C₁₋₃-alkyl)amino-C₁₋₃-alkyloxy,        pyrrolidin-1-yl-C₁₋₃-alkyloxy,        2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyloxy,        piperidin-1-yl-C₁₋₃-alkyloxy,        2-oxo-piperidin-1-yl-C₁₋₃-alkyloxy,        morpholin-4-yl-C₁₋₃-alkyloxy,        3-oxo-morpholin-4-yl-C₁₋₃-alkyloxy,        piperazin-1-yl-C₁₋₃-alkyloxy,        2-oxo-piperazin-1-yl-C₁₋₃-alkyloxy,        3-oxo-piperazin-1-yl-C₁₋₃-alkyloxy,        4-(C₁₋₃-alkyl)piperazin-1-yl-C₁₋₃-alkyloxy,        2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyloxy,        3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyloxy,    -   C₁₋₃-alkylsulfanyl, C₁₋₃-alkysulfinyl, C₁₋₃-alkylsulfonyl,        (het)arylsulfonyl,    -   aminosulfonyl, C₁₋₃-alkyl-aminosulfonyl,        di-(C₁₋₃-alkyl)-aminosulfonyl, pyrrolidin-1-yl-sulfonyl,        piperidin-1-yl-sulfonyl, morpholin-4-yl-sulfonyl,        piperazin-1-yl-sulfonyl, 4-(C₁₋₃-alkyl)piperazin-1-yl-sulfonyl,    -   difluoromethyl, trifluoromethyl, difluoromethoxy,        trifluoromethoxy,    -   2,2,2-trifluoro-1-hydroxyethyl,        2,2,2-trifluoro-1-hydroxy-1-methylethyl,        2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl,    -   C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyloxy,    -   C₃₋₆-cycloalkyl-C₁₋₃-alkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyloxy,    -   (het)aryl, (het)aryloxy, (het)aryl-C₁₋₃-alkyl,        (het)aryl-C₁₋₃-alkyloxy, (het)aryloxy-C₁₋₃-alkyl, or    -   tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,        tetrahydropyran-4-yloxy, tetrahydro-furanyl-C₁₋₃-alkyloxy,        tetrahydropyranyl-C₁₋₃-alkyloxy, thietan-3-yloxy,    -   wherein the above-mentioned (het)aryl groups are phenyl,        naphthyl, or    -   pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl,        benzothiophenyl, quinolinyl, isoquinolinyl, or    -   pyrrolyl, furanyl, thienyl, imidazolyl, pyridyl wherein 1 or 2        CH are replaced by N, or    -   indolyl, benzofuranyl, benzothiophenyl, quinolinyl,        isoquinolinyl wherein 1 to 3 CH are replaced by N, or    -   1,2-dihydro-2-oxo-pyridinyl, 1,4-dihydro-4-oxo-pyridinyl,        2,3-dihydro-3-oxo-pyridazinyl,        1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl,        1,2-dihydro-2-oxo-pyrimidinyl, 3,4-dihydro-4-oxo-pyrimidinyl,        1,2,3,4-tetrahydro-2,4-dioxo-pyrimidinyl,        1,2-dihydro-2-oxo-pyrazinyl,        1,2,3,4-tetrahydro-2,3-dioxo-pyrazinyl,        2,3-dihydro-2-oxo-indolyl, 2,3-dihydrobenzofuranyl,        2,3-dihydro-2-oxo-1H-benzimidazolyl,        2,3-dihydro-2-oxo-benzoxazolyl, 1,2-dihydro-2-oxo-quinolinyl,        1,4-dihydro-4-oxo-quinolinyl, 1,2-dihydro-1-oxo-isoquinolinyl,        1,4-dihydro-4-oxo-cinnolinyl, 1,2-dihydro-2-oxo-quinazolinyl,        1,4-dihydro-4-oxo-quinazolinyl,        1,2,3,4-tetrahydro-2,4-dioxo-quinazolinyl,        1,2-dihydro-2-oxoquinoxalinyl,        1,2,3,4-tetrahydro-3-oxo-quinoxalinyl,        1,2,3,4-tetrahydro-2,3-dioxo-quinoxalinyl,        1,2-dihydro-1-oxo-phthalazinyl,        1,2,3,4-tetrahydro-1,4-dioxo-phthalazinyl, chromanyl,        coumarinyl, 2,3-dihydro-benzo[1,4]dioxinyl,        3,4-dihydro-3-oxo-2H-benzo[1,4]oxazinyl, and    -   wherein all the above-mentioned (het)aryl groups are optionally        substituted with 1, 2, or 3 R¹¹ which may be identical or        different.        (c²): More preferably R⁴ denotes fluorine, chlorine, bromine,        C₁₋₄-alkyl, hydroxy, C₁₋₄-alkyloxy,    -   thietan-3-yloxy,    -   amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino, pyrrolidin-1-yl,        2-oxo-pyrrolidin-1-yl, piperidin-1-yl, 2-oxo-piperidin-1-yl,        morpholin-4-yl, 3-oxo-morpholin-4-yl, piperazin-1-yl,        2-oxo-piperazin-1-yl, 3-oxo-piperazin-1-yl,        4-(C₁₋₃-alkyl)piperazin-1-yl,        4-(C₁₋₄-alkylcarbonyl)-piperazin-1-yl,        4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkyloxycarbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl,        2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,        3-oxo-4-(C₁₋₃-alkyl)piperazin-1-yl,    -   C₁₋₃-alkyl-carbonylamino, (het)arylcarbonylamino,        (het)aryl-C₁₋₃-alkyl-carbonylamino, C₁₋₃-alkyloxy-carbonylamino,        aminocarbonylamino, C₁₋₃-alkyl-aminocarbonylamino,        di-(C₁₋₃-alkyl)aminocarbonylamino,        pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamino,        morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino,        4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonylamino,    -   2-oxo-imidazolidinyl, 1,1-dioxo-[1,2]thiazinanyl,    -   cyano, carboxy, C₁₋₃-alkyloxy-carbonyl, aminocarbonyl,        C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,        pyrrolidin-1-yl-carbonyl,        2-(methoxymethyl)-pyrrolidin-1-yl-carbonyl,        3-(methoxymethyl)-pyrrolidin-1-yl-carbonyl,        piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl,        piperazin-1-yl-carbonyl, 4-(C₁₋₃-alkyl)piperazin-1-yl-carbonyl,        N—(C₁₋₃-alkyl)-(het)arylaminocarbonyl,        N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkylaminocarbonyl,    -   C₁₋₄-alkyl-carbonyl, (het)aryl-carbonyl,    -   C₁₋₃-alkylcarbonyl-C₁₋₃-alkyl, hydroxy-C₁₋₃-alkyl,        C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl,        C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,        pyrrolidin-1-yl-C₁₋₃-alkyl, 2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl,        morpholin-4-yl-C₁₋₃-alkyl,    -   C₁₋₃-alkylsulfonyl, aminosulfonyl,    -   C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl,        (het)arylcarbonylamino-C₁₋₃-alkyl,    -   hydroxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-C₁₋₃-alkyloxy,    -   difluoromethyl, trifluoromethyl, difluoromethoxy,        trifluoromethoxy,    -   2,2,2-trifluoro-1-hydroxyethyl,        2,2,2-trifluoro-1-hydroxy-1-methylethyl,        2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl,    -   (het)aryl, (het)aryl-C₁₋₃-alkyl or (het)aryloxy,    -   wherein the above-mentioned (het)aryl groups are phenyl,        naphthyl, pyrrolyl, furanyl, thienyl, pyridyl, indolyl,        benzofuranyl, benzothiophenyl, quinolinyl, and isoquinolinyl, or    -   pyrrolyl, furanyl, thienyl, imidazolyl, or pyridyl wherein 1 or        2 CH are replaced by N, or    -   indolyl, benzofuranyl, benzothiophenyl, quinolinyl, or        isoquinolinyl wherein 1 to 3 CH are replaced by N, and    -   wherein the above-mentioned (het)aryl groups may be substituted        with 1, 2, or 3 R¹¹ which may be identical or different.        (c³): Even more preferably, R⁴ denotes fluorine, chlorine,        C₁₋₄-alkyl, difluoromethyl, trifluoromethyl, hydroxy,        C₁₋₄-alkyloxy, difluoromethoxy, trifluoromethoxy,        thietan-3-yloxy, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino,        pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl,        C₁₋₃-alkyl-carbonylamino, C₁₋₄-alkylcarbonyl, carboxy, cyano,        C₁₋₃-alkoxycarbonyl, amino-carbonyl, C₁₋₃-alkyl-aminocarbonyl,        di-(C₁₋₃-alkyl)-aminocarbonyl, 2-oxo-pyrrolidin-1-yl,        hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl,        C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,        morpholin-4-yl-C₁₋₃-alkyl, C₁₋₃-alkylcarbonyl-C₁₋₃-alkyl,        C₁₋₃-alkyl-carbonylamino-C₁₋₃-alkyl,        1,1-dioxo-[1,2]thiazinan-2-yl, 2-oxo-imidazolidinyl,        C₁₋₃-alkylsulfonyl, aminosulfonyl, phenyl, pyrazolyl, oxazolyl,        [1,2,4]oxadiazol-3-yl, or tetrazol-1-yl, while the aromatic and        heteroaromatic groups listed are optionally substituted with 1,        2, or 3 groups R¹¹ which may be identical or different.        (c⁴): Most preferably, R⁴ denotes fluorine, chlorine, methyl,        ethyl, iso-butyl, tert-butyl, difluoromethyl, trifluoromethyl,        hydroxy, methoxy, tert-butyloxy, thietan-3-yloxy, amino,        methylamino, acetylamino, hydroxymethyl, acetylaminomethyl,        carboxy, cyano, methoxycarbonyl, aminocarbonyl,        methylaminocarbonyl, 2-oxo-pyrrolidin-1-yl, methylcarbonyl,        2-oxo-imidazolidinyl, methylsulfonyl, aminosulfonyl, phenyl,        pyrazol-3-yl, oxazol-5-yl, 5-methyl-[1,2,4]oxadiazol-3-yl,        tetrazol-1-yl, or tetrazol-5-yl.        d) Definitions (d^(i)) for R⁵ and R⁶, which are linked and bound        to adjacent carbon atoms, in the order of preference, ascending        from preferably (d¹) to more preferably (d²) up to most        preferably (d³):        (d¹): Preferably, R⁵ and R⁶ form a methylenedioxy,        difluoromethylenedioxy, ethylenedioxy, or C₃₋₅-alkylene group.        (d²): More preferably, R⁵ and R⁶ form a methylenedioxy,        difluoromethylenedioxy, ethylenedioxy, propylene, or butylene        group.        (d³): Most preferably, R⁵ and R⁶ form a methylenedioxy,        difluoromethylenedioxy, or 1,2-ethylenedioxy group.        e) Definitions (e^(i)) for R⁷ in the order of preference,        ascending from preferably (e¹) to more preferably (e²) up to        most preferably (e⁴):        (e¹): Preferably, R⁷ denotes halogen, C₁₋₆-alkyl, C_(m)-alkenyl,        C₂₋₆-alkynyl, hydroxy, C₁₋₄-alkyloxy,    -   nitro, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino,        piperidin-1-yl, 2-oxo-piperidin-1-yl, morpholin-4-yl,        3-oxo-morpholin-4-yl, piperazin-1-yl, 2-oxo-piperazin-1-yl,        3-oxo-piperazin-1-yl, 4-(C₁₋₄-alkylcarbonyl)-piperazin-1-yl,        4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkyloxycarbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl,        2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,        3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,    -   C₁₋₃-alkyl-carbonylamino, (het)aryl-carbonylamino,        C₁₋₃-alkyloxy-carbonylamino, aminocarbonylamino,        C₁₋₃-alkyl-aminocarbonylamino,        di-(C₁₋₃-alkyl)aminocarbonylamino,        pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamino,        morpholin-4-yl-carbonylamino, C₁₋₃-alkyksulfonylamino,        C₁₋₃-alkyl-amino-sulfonylamino,        di-(C₁₋₃-alkyl)amino-sulfonylamino,        pyrrolidin-1-yl-sulfonylamino, piperidin-1-yl-sulfonylamino,        morpholin-4-yl-sulfonylamino, (het)arylsulfonylamino,    -   N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-carbonylamino,        N—(C₁₋₃-alkyl)-(het)arylcarbonylamino,        N—(C₁₋₃-alkyl)-C₁₋₃-alkyloxy-carbonylamino,        N-(aminocarbonyl)-C₁₋₃-alkylamino,        N—(C₁₋₃-alkyl-aminocarbonyl)-C₁₋₃-alkylamino,        N-[di-(C₁₋₃-alkyl)aminocarbonyl]-C₁₋₃-alkylamino,    -   N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-sulfonylamino,        N—(C₁₋₃-alkyl)-(het)arylsulfonylamino,    -   cyano, carboxy, C₁₋₃-alkyloxy-carbonyl, aminocarbonyl,        C₁₋₃-alkyl-aminocarbonyl, (C₁₋₃-alkyl)-aminocarbonyl,        pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,        morpholin-4-yl-carbonyl, piperazin-1-yl-carbonyl,        4-(C₁₋₃-alkyl)piperazin-1-yl-carbonyl, (het)arylaminocarbonyl,        N—(C₁₋₃-alkyl)-(het)arylaminocarbonyl,        (het)aryl-C₁₋₃-alkylaminocarbonyl,        N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkylaminocarbonyl,    -   C₁₋₄-alkyl-carbonyl, (het)aryl-carbonyl,    -   carboxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyl,        cyano-C₁₋₃-alkyl, aminocarbonyl-C₁₋₃-alkyl,        C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyl,        di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl,    -   pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl,        piperidin-1-yl-carbonyl-C₁₋₃-alkyl,        morpholin-4-yl-carbonyl-C₁₋₃-alkyl,    -   carboxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyloxy,        cyano-C₁₋₃-alkyloxy, aminocarbonyl-C₁₋₃-alkyloxy,        C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyloxy,        di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy,        pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl-oxy,        piperidin-1-yl-carbonyl-C₁₋₃-alkyloxy,        morpholin-4-yl-carbonyl-C₁₋₃-alkyl-oxy,    -   hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl,        C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,        pyrrolidin-1-yl-C₁₋₃-alkyl, 2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl,        piperidin-1-yl-C₁₋₃-alkyl, 2-oxo-piperidin-1-yl-C₁₋₃-alkyl,        morpholin-4-yl-C₁₋₃-alkyl, 3-oxo-morpholin-4-yl-C₁₋₃-alkyl,        3-oxo-piperazin-1-yl-C₁₋₃-alkyl,        3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,    -   C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl,        arylcarbonylamino-C₁₋₃-alkyl,    -   hydroxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-C₁₋₃-alkyloxy,        C₁₋₃-alkylsulfanyl-C₁₋₃-alkyloxy,        C₁₋₃-alkylsulfinyl-C₁₋₃-alkyloxy,        C₁₋₃-alkylsulfonyl-C₁₋₃-alkyloxy, amino-C₁₋₃-alkyloxy,        C₁₋₃-alkylamino-C₁₋₃-alkyloxy,        di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyloxy,        pyrrolidin-1-yl-C₁₋₃-alkyloxy,        2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyloxy,        piperidin-1-yl-C₁₋₃-alkyloxy,        2-oxo-piperidin-1-yl-C₁₋₃-alkyloxy,        morpholin-4-yl-C₁₋₃-alkyloxy,        3-oxo-morpholin-4-yl-C₁₋₃-alkyloxy,        3-oxo-piperazin-1-yl-C₁₋₃-alkyloxy,        3-oxo-4-(C₁₋₃-alkyl)piperazin-1-yl-C₁₋₃-alkyloxy,    -   C₁₋₃-alkylsulfanyl, C₁₋₃-alkysulfinyl, C₁₋₃-alkylsulfonyl,        (het)arylsulfonyl, trifluoromethylsulfinyl,        trifluoromethylsulfonyl,    -   aminosulfonyl, C₁₋₃-alkyl-aminosulfonyl,        di-(C₁₋₃-alkyl)-aminosulfonyl, pyrrolidin-1-yl-sulfonyl,        piperidin-1-yl-sulfonyl, morpholin-4-yl-sulfonyl,    -   difluoromethyl, trifluoromethyl, difluoromethoxy,        trifluoromethoxy,    -   C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyloxy,    -   C₃₋₆-cycloalkyl-C₁₋₃-alkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyloxy,        (het)aryl, (het)aryloxy, (het)aryl-C₁₋₃-alkyl,        (het)aryl-C₁₋₃-alkyloxy, (het)aryloxy-C₁₋₃-alkyl, or    -   tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,        tetrahydropyran-4-yloxy, tetrahydrofuranyl-C₁₋₃-alkyloxy,        tetrahydropyranyl-C₁₋₃-alkyloxy,    -   wherein the above-mentioned (het)aryl is phenyl, naphthyl,        pyrrolyl, furanyl, thienyl, pyridyl, or    -   pyrrolyl, furanyl, thienyl, imidazolyl, pyridyl in which 1 or 2        CH are replaced by N,    -   and wherein the above-mentioned (het)aryl groups are optionally        substituted with one or two R¹¹ which may be identical or        different.        (e²): More preferably, R⁷ denotes fluorine, chlorine, bromine,    -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, hydroxy, C₁₋₄-alkyloxy,    -   amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino,    -   C₁₋₃-alkyl-carbonylamino, C₁₋₃-alkyloxy-carbonylamino,        aminocarbonylamino, C₁₋₃-alkyl-aminocarbonylamino,        di-(C₁₋₃-alkyl)aminocarbonylamino, C₁₋₃-alkyl-sulfonylamino,    -   N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-carbonylamino,        N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-sulfonylamino,    -   cyano, carboxy, C₁₋₃-alkyloxy-carbonyl, aminocarbonyl,        C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,        pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,        morpholin-4-yl-carbonyl,    -   carboxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyl,        cyano-C₁₋₃-alkyl, aminocarbonyl-C₁₋₃-alkyl,        C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyl,        di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl,    -   carboxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyloxy,        cyano-C₁₋₃-alkyloxy,    -   hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl,        C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,    -   C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl,    -   hydroxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-C₁₋₃-alkyloxy,    -   C₁₋₃-alkylsulfonyl, trifluoromethylsulfonyl,    -   aminosulfonyl, C₁₋₃-alkyl-aminosulfonyl,        di-(C₁₋₃-alkyl)-aminosulfonyl,    -   difluoromethyl, trifluoromethyl, difluoromethoxy,        trifluoromethoxy,    -   C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyloxy,    -   tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,        tetrahydropyran-4-yloxy, tetrahydrofuranyl-C₁₋₃-alkyloxy,        tetrahydropyranyl-C₁₋₃-alkyloxy, or    -   phenyl or phenoxy that are optionally substituted with one or        two identical or different R¹¹.        (e³): Even more preferably, R⁷ denotes fluorine, chlorine,        bromine, C₁₋₄-alkyl, trifluoromethyl, hydroxy, C₁₋₄-alkyloxy,        trifluoromethoxy, phenoxy, carboxy, cyano, C₁₋₃-alkoxycarbonyl,        aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl,        di-(C₁₋₃-alkyl)-aminocarbonyl, or phenyl.        (e⁴): Most preferably, R⁷ denotes fluorine, chlorine, bromine,        methyl, isopropyl, trifluoromethyl, hydroxy, methoxy,        trifluoromethoxy, phenoxy, aminomethyl, carboxy,        methoxycarbonyl, aminocarbonyl, or phenyl.        f) Definitions (f^(i)) for R¹¹ in the order of preference,        ascending from preferably (e) to more preferably (F²) up to most        preferably (f³):        (f¹) Preferably, R¹¹ denotes fluorine, chlorine, bromine,        C₁₋₃-alkyl, difluoromethyl, trifluoromethyl, cyano, nitro,        amino, acetylamino, methylsulfonylamino, carboxy,        C₁₋₄-alkyloxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,        di-(C₁₋₃-alkyl)-aminocarbonyl, methylsulfanyl, methylsulfinyl,        methylsulfonyl, hydroxy, C₁₋₃-alkyloxy, difluoromethoxy, or        trifluoromethoxy.        (f²) More preferably, R¹¹ denotes fluorine, chlorine, methyl,        difluoromethyl, trifluoromethyl, cyano, acetylamino,        methylsulfonylamino, carboxy, C₁₋₃-alkyloxycarbonyl,        aminocarbonyl, methylaminocarbonyl, dimethyl-aminocarbonyl,        hydroxy, or methoxy.        (f³) Most preferably, R¹¹ denotes fluorine, methyl, methoxy,        cyano, or acetylamino.

Each a^(i), b^(i), c^(i), d^(i), e^(i), f^(i) represents acharacterized, individual embodiment for the corresponding substituentas described above. So given the above definitions, preferred individualembodiments of the first aspect of the invention are fully characterizedby the term (a^(i)b^(i)c^(i)d^(i)e^(i)f^(i)) if for each letter i inthis term an individual figure is given. Indices i vary independentlyfrom each other. All individual embodiments described by the term inbrackets with full permutation of indices i, referring to the abovedefinitions, shall be comprised by the present invention.

The following table 1 shows, exemplarily and in the order of increasingpreference from the first line to the last line, such embodiments E-1 toE-18 of the invention that are considered preferred. This means thatembodiment E-18, represented by the entries in the last row of table 1,is the most preferred embodiment.

TABLE 2 Preferred embodiments E-1 to E-18 of the invention R¹ R² R⁴R⁵/R⁶ R⁷ R¹¹ E-1 a¹ b¹ c¹ d¹ e¹ f¹ E-2 a² b² c¹ d² e¹ f² E-3 a² b² c² d²e¹ f³ E-4 a² b² c¹ d² e² f³ E-5 a² b² c² d² e² f³ E-6 a² b³ c² d³ e² f³E-7 a³ b³ c² d³ e² f³ E-8 a³ b³ c³ d³ e² f³ E-9 a³ b³ c² d³ e³ f³ E-10a⁴ b³ c² d³ e² f³ E-11 a⁴ b⁴ c² d³ e² f³ E-12 a⁴ b⁴ c³ d³ e² f³ E-13 a⁴b⁴ c² d³ e³ f³ E-14 a³ b³ c³ d³ e³ f³ E-15 a³ b³ c³ d³ e⁴ f³ E-16 a³ b³c⁴ d³ e³ f³ E-17 a³ b³ c⁴ d³ e⁴ f³ E-18 a⁴ b⁴ c⁴ d³ e⁴ f³including the tautomers, the stereoisomers, the mixtures, and the saltsthereof.

Another preferred embodiment of this invention is described by theformula Ia

wherein the residue R² occupies the endo (=trans to the NCOR¹ residueand cis to the ethylene bridge) position of the bicyclic structure andwherein R¹ and R² are defined as hereinbefore and hereinafter, thetautomers, the stereoisomers, the mixtures, and the salts thereof.

Some terms used above and hereinafter to describe the compoundsaccording to the invention will now be defined more closely.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valence isnot exceeded, and that the substitution results in a stable compound.

The term “optionally substituted with one or more, preferably one tofour, substituents” means that the respective group is unsubstituted orsubstituted with one, two, three or four substituents.

The term “partially unsaturated” as used herein, means that in thedesignated group or moiety 1, 2 or more, preferably 1 or 2, double bondsare present. Preferably as used herein, the term “partially unsaturated”does not cover fully unsaturated groups or moieties.

The term halogen denotes an atom selected from the group consisting ofF, Cl, Br, and I.

The term C_(1-n)-alkyl, wherein n may have a value of 2 to 18, denotes asaturated, branched or unbranched hydrocarbon group with 1 to n C atoms.Examples of such groups include methyl, ethyl, n-propyl, iso-propyl,butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl,neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc.

The term C_(2-n)-alkenyl, wherein n has a value of 3 to 6, denotes abranched or unbranched hydrocarbon group with 2 to n C atoms and a C═Cdouble bond. Examples of such groups include ethenyl, 1-propenyl,2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl etc.

The term C_(2-n)-alkynyl, wherein n has a value of 3 to 6, denotes abranched or unbranched hydrocarbon group with 2 to n C atoms and a CCtriple bond. Examples of such groups include ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,5-hexynyl etc. Unless otherwise stated alkynyl groups are connected tothe remainder of the molecule via the C atom in position 1. Thereforeterms such as 1-propynyl, 2-propynyl, 1-butynyl, etc. are equivalent tothe terms 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, etc. This alsoapplies analogously to C_(2-n)-alkenyl groups.

The term C_(1-n)-alkoxy denotes a C_(1-n)-alkyl-0 group, whereinC_(1-n)-alkyl is as hereinbefore defined. Examples of such groupsinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy,sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy,tert-pentoxy, n-hexoxy, iso-hexoxy etc.

The term C_(1-n)-alkylcarbonyl denotes a C_(1-n)-alkyl-C(═O) group,wherein C_(1-n)-alkyl is as hereinbefore defined. Examples of suchgroups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl,iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl,sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl,iso-pentylcarbonyl, neo-pentylcarbonyl, tert-pentylcarbonyl,n-hexylcarbonyl, iso-hexylcarbonyl, etc.

The term C_(3-n)-cycloalkyl denotes a saturated mono-, bi-, tri- orspirocarbocyclic group with 3 to n C atoms. Examples of such groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3.2.1]octyl,spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc.Preferably the term C₃₋₇-cycloalkyl denotes saturated monocyclic groups.

The term C_(3-n)-cycloheteroalkyl denotes a saturated mono-, bi-, tri-or spirocarbocyclic group with 3-m to n-m C atoms and wherein n denotes3 to 10 and m denotes 1 to 3 heteroatoms independently selected fromNR^(N), O, S, SO, and SO₂, which in addition may have a carbonyl group.Examples of such groups include aziridinyl, oxiranyl, azetidinyl,oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl,tetrahydropyranyl, azepanyl, piperazinyl, morpholinyl,tetrahydrofuranonyl, tetrahydropyranonyl, pyrrolidinonyl, piperidinonyl, piperazinonyl, morpholinonyl. Preferably the termC₃₋₆-cycloheteroalkyl denotes saturated monocyclic groups with one ortwo heteroatoms.

The term C_(5-n)-cycloalkenyl denotes a C_(5-n)-cycloalkyl group whichis as hereinbefore defined and additionally has at least one unsaturatedC═C double bond.

The term C_(3-n)-cycloalkylcarbonyl denotes a C_(3-n)-cycloalkyl-C(═O)group wherein C_(3-n)-cycloalkyl is as hereinbefore defined.

The term heteroaromatic denotes an aromatic structure which has at leastone carbon atom replaced with a heteroatom such as N, O, or S. Examplesof such groups include pyrrolyl, furanyl, thienyl, imidazolyl,pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, indolyl,benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, etc.

The term tri-(C₁₋₄-alkyl)silyl comprises silyl groups which haveidentical or two or three different alkyl groups.

The term di-(C₁₋₃-alkyl)amino comprises amino groups which haveidentical or two different alkyl groups.

If groups or residues are optionally substituted, this applies to anyform of the group or residue. For instance, if an alkyl group isoptionally mono- or polyfluorinated this comprises also alkyl residueswhich are part of larger groups, e.g. alkyloxy, alkylcarbonyl,alkoxyalkyl, etc. Accordingly, in cases where R⁴ or R⁷ has e.g. themeaning alkyloxy, while alkyl residues are optionally mono- orpolyfluorinated, the meanings difluoromethoxy and trifluoromethoxy arealso comprised. The same applies to groups or residues in which a CH₂group may be replaced by O, S, NR, CO, or SO₂. For instance, a residuehaving inter alia the meaning hydroxy-C₁₋₃-alkyl, in which a CH₂ groupmay be replaced by CO, this comprises carboxy, carboxymethyl,hydroxymethylcarbonyl, carboxyethyl, hydroxymethylcarbonylmethyl, andhydroxyethylcarbonyl.

All atoms/elements, including atoms that are part of a group, describedherein comprise all stable isotopic forms of the respective element. Forinstance, whenever hydrogen is mentioned, either explicitly or as partof a group such as methyl, this includes hydrogen and deuterium asstable isotopic forms of the element hydrogen.

The compounds according to the invention may be obtained using methodsof synthesis known in principle. Preferably the compounds are obtainedby the following methods according to the invention which are describedin more detail hereinafter.

Scheme 1 summarizes different approaches to prepare the nortropaneskeleton from butan-1,4-dione or a cyclic congener thereof and1,3-acetonedicarboxylic acid, acetoacetic acid ester, or derivativesthereof. Reactions 1.) and 3.) represent an example of combiningsuccinaldehyde, 1,3-acetonedicarboxylic acid diester or acetoacetic acidester and an amine, e.g. a protected ammonia equivalent such asbenzylamine or methylamine, to obtain3-oxo-8-aza-bicyclo[3.2.1]octane-2,4-dicarboxylic acid diesters asintermediates. Reaction 1.) is preferably carried out in an alcohol,such as methanol, ethanol or benzyl alcohol, or an aqueous solvent.Preferred co-solvents are N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidinone, dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane,or 1,2-dimethoxyethane (see e.g. J. Chem. Soc. 1917, 111, 766;Tetrahedron Asymmetry 2002, 21, 2351-2358; U.S. Pat. No. 2,845,427, 1955and U.S. Pat. No. 2,836,598, 1954; patent, DE 352981 and DE 354950; andreferences quoted therein). The reactions may also be carried outwithout an additional solvent or in one of the co-solvents mentioned.The transformation may be conducted without an additive but often thepresence of a base, such as sodium hydroxide, methoxide, ortert-butoxide, or an acid, such as hydrochloric acid, is advantageous oreven essential. Using a base or an acid as additive may result in thedirect formation of the N-substituted nortropanone depending on thealkyl ester used. The reactions are carried out at −30 to 160° C.,preferably between −10 and 120° C. The carboxy groups may be removedafter basic or acidic hydrolysis of the ester groups at temperaturesbetween 10 and 140° C. Since the same solvents may be applied as for thepreceding step, the reaction may be carried out in the same reactionpot. Reaction 3.) may be conducted as described for 1.), preferably inthe presence of an alkali metal hydroxide in an aqueous or alcoholicsolution (see e.g. patent DE 345759). Equation 2.) shows an exampleusing a dialkoxytetrahydrofuran as a succinaldehyde surrogate to preparethe nortropanone framework (see e.g. J. Am. Chem. Soc. 1952, 74,3825-3828; Helv. Chim. Acta 1986, 69, 887-897; J. Heterocycl. Chem.1992, 29, 1541-1544; Helv. Chim. Acta 2003, 86, 812-826; and citationsquoted therein). These reactions are preferably carried out with1,3-acetonedicarboxylic acid and an amine, such as e.g. benzylamine,methylamine, or 4-methoxyaniline, in water that may be combined withalcohols, e.g. methanol or ethanol, N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide,tetrahydrofuran, 1,4-dioxane, or 1,2-dimethoxyethane. The overalltransformation consists of three reaction steps: liberation ofsuccinaldehyde from the precursor, reaction of succinaldehyde with theamine followed by the reaction with 1,3-acetonedicarboxylic acid(Mannich reaction) and eventually decarboxylation of the carboxylgroups. Accordingly, the reaction conditions, primarily the pH value ofthe solution, have to be adjusted over the course of the sequence.Liberation of succinaldehyde from the precursor is preferably done bythe treatment with acid, e.g. hydrochloric acid, sulfuric acid, orphosphoric acid, at temperatures of −10 to 60° C. Then, the amine and1,3-acetonedicarboxylic acid are added and the pH value of the solutionis raised by the addition of additives, e.g. alkali metal acetate,citrate, phosphate, or hydrogenphosphate; this step is preferablyconducted between −10 and 60° C. The eventual decarboxylation isachieved by increasing the temperature, preferably to 30 to 140° C.;lowering the pH value, using e.g. hydrochloric acid, may beadvantageous. Nortropanone may also be prepared from N-protected2,5-dialkoxypyrrolidine and a diene or an silyl enol ether asexemplified in equations 4.) and 5.) (see e.g. Chem. Commun. 2002,2626-2627; Synlett 2004, 143-145; and references quoted therein). Thesereactions are carried out under anhydrous conditions in an inert solventsuch as dichloromethane, 1,2-dichloroethane, fluorinated hydrocarbons,ether, 1,4-dioxane, benzene, toluene, or hexane. The presence of a Lewisacid, such as trimethylsilyl triflate (=trifluoromethanesulfonate),boron trifluoride etherate, or a lanthanide triflate, is essential topromote the reactions. Preferably, the reactions are performed attemperatures between −78 and 100° C.

Another viable synthetic route to the nortropanone scaffold isdelineated in Scheme 2. Key reaction is the addition of an amine, e.g.benzylamine, methyl amine, 4-methoxyaniline, or hydroxylamine, tocycloheptadienone (see e.g. J. Am. Chem. Soc. 1989, 111, 4433-4440; J.Am. Chem. Soc. 2002, 124, 2245-2258; and references cited therein). Thisreaction is preferably carried out in an alcohol, e.g. methanol orethanol, that may be combined with solvents such as water,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone,dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, ether, or1,2-dimethoxyethane, at temperatures ranging from 0 to 120° C.Beneficial additives may be bases such as e.g. potassium carbonate,calcium oxide, triethylamine, ethyldiisopropylamine,diazabicycloundecene, or alkali metal alkoxides. Cyclohepta-2,6-dienonemay be obtained from cycloheptanone as described (see e.g. J. Am. Chem.Soc. 2002, 124, 2245-2258 and references cited therein).

Residue R² or a precursor of it may be introduced as described in Scheme3; R² has the meanings as defined hereinbefore and hereinafter. Additionof a magnesium halide or lithium derivative of R² to an N-protectednortropanone delivers the corresponding nortropanol. This transformationis preferably conducted in ether, 1,4-dioxane, 1,2-dimethoxyethane,benzene, toluene, tetrahydrofuran, hexane, N-methylpyrrolidinone,dimethylsufoxide, or mixtures thereof at temperatures between −80 and60° C., preferably between −50 and 40° C. The subsequent dehydrationreaction to acquire the nortropene derivative may be performed using anacid, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, orphosphoric acid, a dehydrating reagent such as Burgess' reagent orMartin's sulfurane, or a sulfonyl chloride or anhydride in combinationwith a base such as methylsulfonyl chloride and triethylamine, thionylchloride and pyridine, or trifluoromethanesulfonic anhydride andpyridine. The reaction using an acid are preferably conducted in aqueousor alcoholic solutions that may contain co-solvents, e.g.tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, 1,4-dioxane,1,2-dimethoxyethane, acetonitrile, or N-methylpyrrolidinone, attemperatures between 10 and 140° C. The conversion employing andehydrating reagent is preferably conducted in an inert solvent such asdichloromethane, 1,2-dichloroethane, benzene, toluene, hexane,tetrahydrofuran, 1,4-dioxane, or 1,2-dimethoxyethane, at −30 to 140° C.,preferably at −10 to 120° C. The double bond is subsequentlyhydrogenated to give the derivatized nortropane. Competent catalysts forthe hydrogenation using hydrogen may be e.g. platinum oxide, palladiumon carbon, palladium hydroxide, Raney nickel, rhodium, ruthenium, andClRh(PPh₃)₃. The hydrogenation is carried out at temperatures between 0and 180° C., preferably between 10 and 120° C., and at hydrogenpressures between 1 and 10 bar, preferably between 1 and 6 bar. Suitedsolvents may be ethyl acetate, alcohols, e.g. methanol or ethanol,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,N-methylpyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide,dichloromethane, hexanes, toluene, benzene, dimethlylsulfoxide,acetonitrile, acetic acid, or mixtures thereof. Beneficial additives maybe acids such as hydrochloric acid, sulfuric acid, methanesulfonic acid,trifluoroacetic acid, or acetic acid. The one-step conversion of thenortropanol derivative to the nortropane may also be feasible. Thistransformation may be carried out using hydrogen in the presence of atransition metal as described above, preferably in the presence of anacid. Alternatively, the reduction may be performed with a hydridesource such as a silane, e.g. triethylsilane, borohydride, e.g. sodiumborohydride, triacetoxyborohydride, or cyanoborohydride, aluminumhydride, e.g. lithium aluminumhydride, in the presence of a Lewis acidsuch as boron trifluoride, trimethylsilyl triflate, aluminum chloride,alkylaluminum dichloride, dialkylaluminum chloride, lanthanidetriflates, scandium triflate, trifluoroacetic acid, or triflic acid.Preferred solvents for the latter process may be dichloromethane,1,2-dichloroethane, 1,4-dioxane, 1,2-dimethoxyethane, hexanes, toluene,benzene, chlorobenzene, and acetonitrile that are preferably used attemperatures between −30 and 180° C., more preferably between 0 and 140°C. The latter conditions are suited for electron-rich aromatic R²residues.

The reduction from nortropanol or nortropene to nortropane may givemixtures of isomers (endo and exo) depending on the protective groupused on the nitrogen and the reaction conditions. Mixtures of isomerscan be separated into the pure isomers by chromatography, distillation,or crystallization as described above. The entire sequence sketched inScheme 3 is concluded by the removal of the protective group that may beaccomplished as described hereinbefore.

Scheme 4 depicts another synthetic route to the respectively derivatizednortropanes; R² has the meanings as defined hereinbefore andhereinafter. Starting with the N-protected nortropanone thecorresponding enol trifluoromethanesulfonates (=triflate) may beaccessed by treatment of the ketone with a base such as e.g. alkalimetal hexamethyldisilylamide, alkali metal diisopropylamide, lithium2,2,6,6-tetramethylpiperidide, tert-butyllithium, trityllithium,ethyldiisopropylamine, triethylamine, or1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and trapping the enolate withan trifluoromethylsulfonyl electrophile equivalent such as triflicanhydride (F₃CSO₂OSO₂CF₃), F₃CSO₂Cl, PhNTf₂, or ArNTf₂ (Ar=e.g. pyridylor chloropyridyl; Tf=F₃CSO₂). The reaction may be conducted in solventssuch as e.g. tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, ether,dichloromethane, benzene, toluene, hexanes, or mixtures thereof attemperatures between −80 and 80° C., preferably between −70 and 40° C.Additives such as pyridine, 4-dimethylaminopyridine, lithium chloride,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, orhexamethylphosphoramide may be beneficial. Attachment of the residue R²may be accomplished by treatment of the enol triflate with anappropriately derivatized R² in the presence of a transition metalcatalyst.

Appropriate R² are derived from e.g. lithium (R²Li), magnesium, e.g.R²MgCl or Br, zinc, e.g. R²ZnCl/I/Br, boronic acid [R²B(OH)₂], boronicesters, e.g. R²B(OMe)₂ or R²B(OCMe₂CMe₂O), trifluoroborates, e.g.R²BF₃K, silanes, e.g. R²SiF₃, or stannanes, e.g. R²SnBu₃ or R²SnMe₃.Suited transition metal catalysts may be derived from palladium, copper,iron, and nickel that may be used as e.g. salts, complexes, or elementalmodifications. Complexes can be formed in situ or prior to the additionof the transition metal to the reaction mixture. The ligands in thecomplexes of the transition metal may be e.g. phosphines, e.g.triphenylphosphine, tritolylphospine, trifurylphosphine, substituted(2-phenyl-phen-1-yl)-dicyclohexylphosphines, substituted(2-phenyl-phen-1-yl)-di-(tert-butyl)-phosphines,tri-tert-butylphosphine, tri-cyclohexylphosphine,1,1′-bis(diphenylphosphino)-ferrocene, phosphites, 1,3-disubstituteddihydroimidazolium carbenes, 1,3-disubstituted imidazolium carbenes,nitriles, e.g. acetonitrile or benzonitrile, and alkenes, e.g.benzylideneacetone or allyl. Elemental forms of the transition metalsmay be e.g. metal on charcoal or nanoparticles of the transition metal.Suitable salts may comprise e.g. halides, trifluoromethanesulfonates,acetates, or trifluoroacetates. The reaction is preferably carried outin an inert organic solvent or mixtures thereof. Suitable solvents maybe e.g. tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, hexane,toluene, benzene, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidinone, acetone, acetonitrile, ethyl acetate, water,methanol, ethanol, propanol, isopropanol, ethylene glycol, andpolyethylene glycol. The coupling reactions are preferably carried outbetween −80 and 180° C., more preferably at −20 to 120° C. Beneficialadditives may be alkali metal salts, e.g. lithium chloride,tetraalkylammonium salts, e.g. tetrabutylammonium fluoride or hydroxide,silver salts, e.g. silver trifluoromethanesulfonate, copper salts, e.g.copper iodide or copper thiophenecarboxylate, or bases, e.g. alkalimetal hydroxides, potassium carbonate, alkali metal alcoxides, or alkalimetal fluorides. The presented coupling approach to introduce R² is notrestricted to enol trifluoromethanesulfonates derived from nortropanonesbut may also be conducted using the corresponding alkenyl chlorides,bromides, or iodides. The concluding steps in Scheme 4 have beendescribed above.

The synthetic routes presented may rely on the use of protecting groups.Suitable protecting groups for the respective functionalities and theirremoval have been described hereinbefore and may analogously be employed(see also: Protecting Groups, Philip J. Kocienski, 3^(rd) edition, GeorgThieme Verlag, Stuttgart, 2004 and references quoted therein).

Compounds according to the invention obtained by the synthetic routesdescribed may be subsequently converted into other compounds of theinvention by routine processes applicable for conversion of functionalgroups. Examples for subsequent conversion processes are provided in thefollowing paragraphs.

If in the process of manufacture according to the invention a compoundof general formula I is obtained which contains an amino, alkylamino, orimino group, this may be converted by acylation or sulfonylation into acorresponding acyl or sulfonyl compound of general formula I;

if a compound of general formula I is obtained which contains an amino,alkylamino, or imino group, this may be converted by alkylation orreductive alkylation into a corresponding alkyl compound of generalformula I;if a compound of general formula I is obtained which contains a nitrogroup, this may be converted by reduction into a corresponding aminocompound;if a compound of general formula I is obtained which contains an iminogroup, this may be converted by nitrosation and subsequent reductioninto a corresponding N-amino-imino compound;if a compound of general formula I is obtained which contains aC₁₋₃-alkyloxycarbonyl group, this may be converted by cleavage of theester into the corresponding carboxy compound;if a compound of general formula I is obtained which contains a carboxygroup, this may be converted by esterification into a correspondingester of general formula I;if a compound of general formula I is obtained which contains a carboxyor ester group, this may be converted by reaction with an amine into acorresponding amide of general formula I;if a compound of general formula I is obtained which contains a cyanogroup, this may be converted by hydrolysis into the correspondingcarboxy compound;if a compound of general formula I is obtained which contains anaromatic substructure, this may be derivatized by an electrophilicsubstitution reaction with a chlorine, bromine, or iodine atom or anitro, SO₃H, or acyl group to a corresponding compound of generalformula I;if a compound of general formula I is obtained which contains anaromatic amino group, this may be transformed into a correspondingcyano, fluoro, chloro, bromo, iodo, hydroxy, mercapto, or azido compoundof general formula I by diazotization and subsequent replacement of thediazo group with cyanide, fluoride, chloride, bromide, iodide,hydroxide, alkyl or hydrogen sulfide, or azide, respectively;if a compound of general formula I is obtained which contains anaromatic amino group, this may be converted into a corresponding arylderivatized aromatic compound of general formula I by diazotization andsubsequent replacement of the diazo group with an appropriate arylnucleophile mediated by a suited transition metal species;if a compound of general formula I is obtained which contains anaromatic chloro, bromo, iodo, trifluoromethylsulfonyloxy, mesyloxy, ortosyloxy group, this may be converted into a corresponding aryl,alkenyl, alkynyl, or alkyl derivatized compound of general formula I byreplacement of the respective group by aryl, alkenyl, alkynyl, or alkylusing a transition metal species mediated process;if a compound of general formula I is obtained which contains twoheteroatoms at adjacent carbon atoms that are amino and hydroxy, amino,or mercapto, these heteroatoms may be linked via a carboxy carbon atomto form a cyclic amidine, imino ester, or imino thioester substructurethat may be part of an aromatic ring;if a compound of general formula I is obtained which contains a cyanogroup, this may be converted into an amino alkyl derivatized compound ofgeneral formula I by reduction;if a compound of general formula I is obtained which contains a cyanogroup, this may be converted into a N-hydroxycarbamimidoyl group by thetreatment with hydroxylamine;if a compound of general formula I is obtained which contains aN-hydroxycarbamimidoyl group, this may be converted to an oxadiazolederivatized compound of general formula I by the treatment with acarboxylic or related group;if a compound of general formula I is obtained which contains anaminocarbonyl group, this may be converted by dehydration into acorresponding cyano compound of general formula I;if a compound of general formula I is obtained which contains a keto oraldehydic group, this may be converted by reduction into a correspondinghydroxyl compound of general formula I;if a compound of general formula I is obtained which contains anaromatic trialkylsilyl group, this may be converted into a correspondingchloro, bromo, or iodo compound of general formula I by electrophilicdisplacement of the silyl group; and/orif a compound of general formula I is obtained which contains anaromatic alkyloxy group, this may be converted into a correspondinghydroxy compound of general formula I.

The subsequent esterification is optionally carried out in a solvent ormixture of solvents such as methylene chloride, N,N-dimethylformamide,benzene, toluene, chlorobenzene, tetrahydrofuran,benzene/tetrahydrofuran or 1,4-dioxane or particularly advantageously ina corresponding alcohol, optionally in the presence of an acid such ashydrochloric acid, isobutyl chloroformate, thionyl chloride,trimethylchlorosilane, sulfuric acid, methanesulfonic acid,p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide,N,N′-dicyclo-hexylcarbodiimide,N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide,1-hydroxy-benzo-triazole, 4-dimethylamino-pyridine,N,N′-carbonyldiimidazole, triphenylphosphine/carbon tetrachloride, orcombinations thereof, conveniently at temperatures between 0 and 150°C., preferably at temperatures between 0 and 80° C.

The subsequent ester formation may also be carried out by reacting acompound which contains a carboxy group with a corresponding alkylhalide in the presence of a base such as cesium carbonate, potassiumcarbonate, triethylamine, sodium hydroxide, or sodium methoxide. Polarsolvents such as N,N-dimethylformamide, N-methylpyrrolidinone, alcohol,e.g. methanol or ethanol, water, acetonitrile, or tetrahydrofuran arepreferred at temperatures between 10 and 120° C.

The subsequent acylation or sulfonylation is optionally carried out in asolvent or mixture of solvents such as methylene chloride,N,N-dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran,benzene/tetrahydrofuran, or 1,4-dioxane with a corresponding acyl orsulfonyl derivative, optionally in the presence of a tertiary organicbase or an inorganic base, and/or in the presence of isobutylchloroformate, thionyl chloride, trimethylchlorosilane, sulfuric acid,methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride,P₂O₅, N,N′-dicyclohexylcarbodiimide, N,N′-carbonyldiimidazole,N,N′-dicyclohexyl-carbodiimide/N-hydroxysuccinimide,1-hydroxy-benzotriazole, 4-dimethylamino-pyridine,triphenylphosphine/carbon tetrachloride, or combinations thereof. Thetransformation is carried out at temperatures between 0 and 150° C.,preferably at temperatures between 0 and 80° C.

The subsequent alkylation is optionally carried out in a solvent ormixture of solvents such as methylene chloride, N,N-dimethylformamide,benzene, toluene, chlorobenzene, tetrahydrofuran,benzene/tetrahydrofuran, or 1,4-dioxane with an alkylating agent such asa corresponding halide or sulfonic acid ester, e.g. methyl iodide, ethylbromide, dimethylsulfate, or benzyl chloride, optionally in the presenceof a tertiary organic base or an inorganic base at temperatures between0 and 150° C., preferably at temperatures between 0 and 100° C.

The subsequent reductive alkylation is carried out with a correspondingcarbonyl compound such as e.g. formaldehyde, acetaldehyde,propionaldehyde, acetone, or butyraldehyde in the presence of a complexmetal hydride such as sodium borohydride, lithium borohydride, sodiumtriacetoxyborohydride, or sodium cyanoborohydride conveniently at a pHvalue of 6-7 and at ambient temperature or in the presence of ahydrogenation catalyst, e.g. with hydrogen in the presence ofpalladium/charcoal, at a hydrogen pressure of 1 to 5 bar. Themethylation may also be carried out in the presence of formic acid or aformate as reducing agent at elevated temperature, e.g. between 60 and120° C.

The subsequent reduction of a nitro group is carried out, for example,with hydrogen and a metal catalyst such as palladium on carbon, platinumdioxide, or Raney nickel, or using other reducing agents such as iron orzinc in the presence of an acid such as acetic acid.

The subsequent nitrosation of an imino group followed by reduction toobtain the N-amino-imino compound is carried out, for example, with analkyl nitrite such as isoamyl nitrite to form the N-nitroso-iminocompound that is then reduced to the N-amino-imino compound using, forexample, zinc in the presence of an acid such as acetic acid.

The subsequent cleaving of a C₁₋₃-alkyloxycarbonyl group to obtain thecarboxy group is carried out, for example, by hydrolysis with an acidsuch as hydrochloric acid or sulfuric acid or an alkali metal hydroxidesuch as lithium hydroxide, sodium hydroxide, or potassium hydroxide.

The subsequent amide formation is carried out by reacting acorresponding reactive carboxylic acid derivative with a correspondingamine optionally in a solvent or mixture of solvents such as methylenechloride, N,N-dimethylformamide, benzene, toluene, chlorobenzene,tetrahydrofuran, benzene/tetrahydrofuran, or 1,4-dioxane, while theamine used may simultaneously serve as solvent, optionally in thepresence of a tertiary organic base or an inorganic base or with acorresponding carboxylic acid in the presence of a dehydrating agent.Isobutyl chloroformate, thionyl chloride, trimethylchlorosilane,phosphorus trichloride, P₂O₅, N,N′-dicyclohexylcarbodiimide,N,N′-dicyclohexylcarbodiimide/N-hydroxy-succinimide,N,N′-carbonyldiimidazole, or triphenylphosphine/carbon tetrachloridealone or in combination with 1-hydroxy-benzotriazole and/or4-dimethylamino-pyridine may be used at temperatures between 0 and 150°C., preferably between 0 and 80° C.

The subsequent hydrolysis of a cyano group to obtain the carboxy groupis carried out by treatment with, for example, an acid such ashydrochloric acid, phosphoric acid, or sulfuric acid or an alkali metalhydroxide such as lithium hydroxide, sodium hydroxide, or potassiumhydroxide in an aqueous solution at elevated temperatures, preferablybetween 20 and 160° C.

The subsequent introduction of a chlorine, bromine, or iodine atom ontoan aromatic substructure may be carried out by reacting the aromaticcompound with an appropriate electrophile of the halogen atom. Suitedchlorine and bromine electrophiles may be e.g. N-halosuccinimide, HOCl,HOBr, tert-BuOCl, tert-BuOBr, chlorine, bromine, dibromoisocyanuricacid, pyridinium dichlorobromate, pyridinium tribromide, or sulfurylchloride that may be used alone or in combination with an acid, e.g.hydrochloric acid, hydrobromic acid, tetrafluoroboric acid, triflicacid, sulfuric acid, or acetic acid, or a Lewis acid, e.g. iron(III)halide, boron trifluoride hydrate, boron trifluoride etherate, oraluminum halide. Further useful combinations may be LiBr/ceric ammoniumnitrate, KCl or KBr with Oxone®, or KBr/sodium perborate. Suited iodineelectrophiles may be generated from iodine combined with an oxidizingagent such as nitric acid, sulfur trioxide, manganese dioxide, HIO₃,hydrogen peroxide, sodium periodate, peroxydisulfates, and Oxone®.Further suited iodine electrophiles may be e.g. iodine chloride,dichloroiodates, and N-iodosuccinimide. These iodine electrophiles maybe used without an additive or in the presence of an acid such as e.g.acetic acid, trifluoroacetic acid, or sulfuric acid, or a Lewis acidsuch as borontrifluoride hydrate, or copper salts. If a nitro group isto be introduced appropriate nitro electrophiles may be generated from,for example, nitric acid, acetyl nitrate, ceric ammonium nitrate, sodiumnitrate, N₂O₅, alkyl nitrate, and nitronium tetrafluoroborate. Some ofthese reagents may be used without an additive though several of themare better used in combination with an acid, e.g. sulfuric acid ortriflic acid, acetic anhydride, trifluoroacetic anhydride, Lewis acids,e.g. ytterbium triflate or iron acetate, P₂O₅, or a base. The SO₃H groupmay be introduced by reacting the aromatic compound with, for example,concentrated sulfuric acid, SO₃, ClSO₃H, or ClSO₂NMe₂ combined withindium triflate. Acylation of the aromatic part is conducted using anacyl electrophile that may be generated from the respective acyl halide,e.g. chloride, or acyl anhydride and a Lewis acid such as e.g. aluminumhalide, diethylaluminum halide, indium halide, iron(III) halide, tin(IV)halide, boron trifluoride, titanium(IV) halide, or a Brønsted acid, e.g.sulfuric acid or triflic acid. The formyl group is best introduced usingthe so-called Vilsmeier or Vilsmeier-Haack conditions: dialkylformamidecombined with phosgene, thionyl chloride, POCl₃, or oxalyl chloride.Preferred solvents for the electrophilic substitutions described maydiffer depending on the electrophile employed; in the following somemore generally applicable are mentioned: methylene chloride,dichloroethane, chlorobenzene, dichlorobenzene, ether, fluorinatedhydrocarbons, hexanes, quinoline, or acetonitrile. The temperaturespreferably applied range from 0 and 180° C.

The subsequent replacement of an aromatic amino group is initiated bydiazotization of the amino group using a nitrous acid or nitrosoniumsource or equivalent such as a nitrite salt combined with an acid, e.g.sodium nitrite and hydrochloric acid, nitrosonium tetrafluoroborate, oran alkylnitrite, e.g. tert-butyl nitrite or iso-amyl nitrite. Thediazotization is optionally carried out in methylene chloride,dichloroethane, N,N-dimethylformamide, N-methylpyrrolidinone, benzene,toluene, chlorobenzene, tetrahydrofuran, water, ethyl acetate, alcohol,ether, dimethoxyethane, dioxane, or mixtures thereof at temperaturesbetween −10° C. and 100° C. (diazotization of amino groups is detailedin, for example, Angew. Chem. Int. Ed. 1976, 15, 251). The subsequentdisplacement of the diazo group by a cyano group, bromine, or chlorineatom using cuprous cyanide, chloride, or bromide, respectively, is knownas the Sandmeyer reaction (see e.g. March's Advanced Organic Chemistry,Michael B. Smith and Jerry March, John Wiley & Sons Inc., 6. Ed., NewJersey, 2007 and references quoted therein); the reaction is optionallyconducted between −10° C. and 120° C. in one of the solvents or mixturesmentioned above. The replacement of the diazo group by a fluorine atommay be achieved with a tetrafluoroborate salt or tetrafluoroboric acidand heating to 20 to 160° C.; the transformation is called Schiemannreaction. Iodine may be introduced by treatment of the diazo compoundwith an iodide salt, e.g. sodium iodide, preferably using water or anaqueous solvent mixture at temperatures between 0 and 120° C. The diazogroup is replaced with hydroxy using water or an aqueous solvent mixtureat temperatures between 0 and 180° C. The reaction often works withoutfurther additives but the addition of cuprous oxide or strong acid maybe advantageous. Mercapto or alkylmercapto may be introduced via theircorresponding disulfide salts or dialkyldisulfides at temperaturesbetween 0 and 120° C.; depending on the sulfur species used an inertsolvent or aqueous solvent system may be preferred (see e.g. Synth.Commun. 2001, 31, 1857 and references quoted therein).

The subsequent replacement of an aromatic amino group by an aryl groupmay be carried out via the corresponding diazo compound obtainable asdescribed above. The reaction with an aryl nucleophile, preferably anaryl boronic acid, boronic ester, trifluoroborate, zinc halide, orstannane, is conducted in the presence of a transition metal speciesderived from e.g. palladium, nickel, rhodium, copper, or iron,preferably palladium. The active catalyst may be a complex of thetransition metal with ligands such as e.g. phosphines, phosphites,imidazole carbenes, imidazolidine carbenes, dibenzylideneacetone, allyl,nitriles, an elemental form of the transition metal such as palladium oncarbon or nanoparticles, or salts such as chloride, bromide, acetate, ortrifluoroacetate. In these reactions the diazo compound is preferablyemployed as its tetrafluoroborate salt optionally in methylene chloride,N,N-dimethylformamide, N-methylpyrrolidinone, benzene, toluene,tetrahydrofuran, water, ethyl acetate, alcohol, ether,dimethylsulfoxide, 1,2-dimethoxyethane, 1,4-dioxane, or mixtures thereofat temperatures between 10 and 180° C., preferably between 20 and 140°C.

The subsequent replacement of an aromatic chloro, bromo, or iodo atom oran aromatic trifluoromethylsulfonyloxy, mesyloxy, or tosyloxy group byan aryl, alkenyl, alkynyl, or alkyl residue is preferably mediated by atransition metal species derived from palladium, nickel, rhodium,copper, or iron. The active catalyst may be a complex of the transitionmetal with ligands such as e.g. phosphines [e.g.tri-tert-butylphosphine, tricyclohexylphosphine, substitutedbiphenyldicyclohexyl-phosphines, substituted(2-phenyl-phenyl)-di-tert-butyl-phosphines, substituted(2-phenyl-phenyl)-dicyclohexyl-phosphines, triphenylphosphine,tritolylphosphine, trifurylphosphine,1,1′-bis(diphenylphosphino)ferrocene], phosphites, imidazole carbenes,imidazolidine carbenes, dibenzylideneacetone, allyl, nitriles, anelemental form of the transition metal such as palladium on carbon ornanoparticles of iron or palladium, or salts such as fluoride, chloride,bromide, acetate, triflate, or trifluoroacetate. The replacement ispreferably conducted with a trifluoroborate, boronic acid, or boronicester (Suzuki or Suzuki-type reaction), zinc halide (Negishi orNegishi-type reaction), stannane (Stille or Stille-type reaction),silane (Hiyama or Hiyama-type reaction), or magnesium halide (Kumada orKumada-type reaction) of the aryl, alkenyl, or alkyl residue to beintroduced. The terminal alkyne is preferably used as it is or as zincacetylide derivative. Depending on the electrophilic and nucleophilicreaction partners additives such as halide salts, e.g. lithium chloride,potassium fluoride, tetrabutylammonium fluoride, hydroxide sources suchas potassium hydroxide or potassium carbonate, silver salts such assilver oxide or triflate, copper salts such as copper chloride or copperthiophenecarboxylate may be advantageous or even essential. Copperiodide is a preferred additive in the coupling with a terminal alkynegroup (Sonogashira reaction). The coupling reactions are optionallyconducted in methylene chloride, N,N-dimethylformamide,N-methylpyrrolidinone, benzene, toluene, tetrahydrofuran, water, ethylacetate, alcohol, ether, dimethylsulfoxide, 1,2-dimethoxyethane,1,4-dioxane, or mixtures thereof, though, depending on the nucleophilesome of them are less or not suited at all. Preferred temperatures arein the range from −10 to 180° C.

The subsequent cyclization of two heteroatoms at adjacent carbon atomsis optionally conducted with a carboxy equivalent such as a nitrile,carboxylic chloride or fluoride, carboxylic acid, ketene, carboxylicester, or carboxylic thioester. The overall transformation consists oftwo reaction steps: attachment of the carboxy equivalent to one of thetwo heteroatoms followed by cyclization with the other heteroatom. Thefirst step is an amide formation with the amino functionality that maybe carried out as described hereinbefore. The ensuing reaction step,cyclization with the second heteroatom, may be accomplished by heatingin the presence of an acid, e.g. acetic acid, trifluoroacetic acid,sulfuric acid, or hydrochloric acid, or a base, e.g. sodium hydroxide,sodium ethoxide, or sodium tert-butoxide. The use of dehydratingreagents such as anhydrides, e.g. acetic anhydride, orthoesters, e.g.trimethyl orthoformate, thionyl chloride, phosgene, diphosgene,triphosgene, phosphorus oxychloride, phosphorus pentachloride,dialkylcarbodiimides, combinations of phosphines, e.g.triphenylphosphine or trialkylphosphine, with dialkyl azodicarboxylates,bromine, iodine, or 1,2-dihaloethanes, e.g.1,2-dibromotetrafluoroethane, is also possible. The reactions arepreferably carried out in inert solvents such as methylene chloride,dichloroethane, benzene, toluene, tetrahydrofuran, ether, orcombinations thereof, though, cyclization in the presence of an acid ora base may also be conducted in water or alcohol, e.g. methanol,ethanol, iso-propanol, or tert-butanol, or combinations with thesesolvents. The reactions are carried out at temperatures between 0 and200° C., preferably between 20 and 140° C.

The subsequent reduction of a cyano group to obtain an aminomethyl groupis optionally conducted with hydrogen in the presence of a transitionmetal species or with a hydride. Suited transition metals may be derivedfrom palladium, nickel, platinum, rhodium, or ruthenium such as, forexample, palladium on charcoal, palladium hydroxide, platinum oxide, orRaney nickel that may be used in solvents such as ethyl acetate,alcohols, e.g. methanol or ethanol, dichloromethane, tetrahydrofuran,ether, benzene, toluene, N,N-dimethylformamide, or N-methylpyrrolidinoneat hydrogen pressures between 1 and 10 bar, preferably between 1 and 5bar, and at temperatures between 0 and 180° C., preferably between 20and 120° C. Additives such as acids, e.g. hydrochloric acid,methanesulfonic acid, sulfuric acid, or acetic acid, may be beneficialfor the hydrogenation. Appropriate hydride sources may be selected frome.g. borohydrides, e.g. sodium borohydride, potassiumtri-sec-butylborohydride, borane, or lithium triethylborohydride, oralanates, e.g. lithium aluminum hydride, or diisobutylaluminum hydride.Some of these reagents are best used in combination with nickel chlorideor cobalt chloride as sodium borohydride. These reagents may be used ine.g. tetrahydrofuran, ether, 1,4-dioxane, 1,2-dimethoxyethane,dichloromethane, 1,2-dichloroethane, benzene, or toluene; some are alsocompatible with alcoholic solutions. Preferred reaction temperaturesrange from −80 to 160° C., more preferably, from −40 to 60° C.

The subsequent formation of an N-hydroxycarbamimidoyl group from a cyanogroup may be carried out by the treatment of the cyano compound withhydroxylamine. The reaction is preferably conducted in aqueous oralcoholic solvents at temperatures between 0° C. and 140° C.

The subsequent formation of an oxadiazole from an N-hydroxycarbamimidoylis optionally conducted with a carboxy equivalent such as nitrile,carboxylic chloride or fluoride, carboxylic acid, ketene, carboxylicester, or carboxylic thioester. The transformation is related to theformation of a ring starting from two adjacent heteroatoms describedabove and may be carried out analogously.

The subsequent formation of a cyano group from an amino carbonyl groupis optionally conducted by using a dehydrating reagent such as e.g.anhydride, e.g. acetic anhydride, trifluoroacetic anhydride, or triflicanhydride, phosgene, thionyl chloride, oxalyl chloride, POCl₃, PCl₅,P₄O₁₀, triphenyl phosphite, or triphenyl- or trialkylphosphine combinedwith tetrachloromethane, 1,2-dibromotetrafluoroethane, or bromine. Thereactions are preferably carried out in dichloromethane,1,2-dichloroethane, hexanes, ether, 1,4-dioxane, benzene, toluene,acetonitrile, mixtures thereof, or without a solvent at temperaturesbetween 0 and 140° C. Additives such as amines, e.g. pyridine ortriethylamine, or N,N-dimethylformamide may be beneficial.

The subsequent reduction of a keto or an aldehydic group to obtain asecondary or primary alcohol may be carried out with a complex metalhydride such as sodium borohydride, lithium borohydride, lithiumtriethylborohydride, diisobutylaluminum hydide, or lithium aluminumhydride. The reductions may be conducted in e.g. dichloromethane,1,2-dichloroethane, hexanes, ether, dioxane, tetrahydrofuran,N,N-dimethylformamide, N-methylpyrrolidinone, benzene, toluene,alcohols, e.g. methanol, water, or mixtures thereof, though, not allreducing agents are compatible with all of these solvents. Preferredtemperatures are between −80 and 140° C. depending on the reducing powerof the reagent. Alternatively, hydrogen in the presence of a transitionmetal catalyst may be used for the reduction.

The subsequent introduction of a chlorine, bromine, or iodine atom bydisplacement of an aromatic silyl group may be carried out by reactingthe aromatic compound with an appropriate electrophile of the halogenatom. For example, N-chloro-, N-bromo, or N-iodo-succinimide, iodinechloride, or bromine are suitable electrophiles for introducing therespective halogen atoms. Dichloromethane, 1,2-dichloroethane,acetonitrile, and acetic acid are among the usable solvents that areemployed at temperatures between 0 and 100° C.

The subsequent cleavage of an alkoxyaryl ether is carried out, forexample, by treatment with boron tribromide in an inert solvent such asdichloromethane or 1,2-dichloroethane at 0 to 80° C. Hydrobromic acid inacetic acid between 0 and 120° C. is another suitable method to cleavearomatic ethers.

In the reactions described hereinbefore, any reactive group present suchas hydroxy, carboxy, amino, alkylamino, or imino may be protected duringthe reaction by conventional protecting groups which are cleaved againafter the reaction.

For example, a protecting group for a hydroxy group may be atrimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, acetyl,pivaloyl, benzoyl, methyl, ethyl, tert-butyl, allyl, trityl, benzyl,4-methoxybenzyl, tetrahydropyranyl, methoxymethyl, ethoxymethyl, or2-trimethylsilylethoxymethyl group,

protecting groups for a carboxy group may be a trimethylsilyl, methyl,ethyl, tert-butyl, allyl, benzyl, or tetrahydropyranyl group,protecting groups for an amino, alkylamino, or imino group may be amethyl, formyl, acetyl, trifluoroacetyl, ethoxycarbonyl,tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxy-benzyl, or2,4-dimethoxybenzyl group and additionally, for the amino group, aphthalyl or tetrachlorophthalyl group, andprotecting groups for a terminal alkyne may be trimethylsilyl,triisopropylsilyl, tertbutyldimethylsilyl, or 2-hydroxy-isopropyl.

Any acyl protecting group may be cleaved, for example, hydrolytically inan aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water,tetrahydrofuran/water, or dioxane/water, in the presence of an acid suchas trifluoroacetic acid, hydrochloric acid, or sulfuric acid or in thepresence of an alkali metal base such as lithium hydroxide, sodiumhydroxide, or potassium hydroxide or aprotically, e.g. in the presenceof iodotrimethylsilane, at temperatures between 0 and 120° C.,preferably between 10 and 100° C. A trifluoroacetyl group is preferablycleaved by treating with an acid such as hydrochloric acid, optionallyin a solvent such as acetic acid, at temperatures between 50 and 120° C.or by treating with sodium hydroxide solution, optionally in anadditional solvent such as tetrahydrofuran or methanol, at temperaturesbetween 0 and 80° C.

Any acetal or ketal protecting group used may be cleaved, for example,hydrolytically in an aqueous solvent, e.g. in water, isopropanol/water,acetic acid/water, tetrahydrofuran/water, or dioxane/water, in thepresence of an acid such as trifluoroacetic acid, hydrochloric acid, orsulfuric acid or aprotically, e.g. in the presence ofiodotrimethylsilane, at temperatures between 0 and 120° C., preferablybetween 10 and 100° C.

A trimethylsilyl group is cleaved, for example, in water, an aqueoussolvent mixture or an alcohol, such as methanol or ethanol, in thepresence of a base such as lithium hydroxide, sodium hydroxide,potassium carbonate, or sodium methoxide.

Acids such as e.g. hydrochloric acid, trifluoroacetic acid, or aceticacid may also be suitable. The cleavage usually takes place atcomparatively low temperatures, e.g. between −60 and 60° C. Silyl groupsother than trimethylsilyl are preferentially cleaved in the presence ofan acid, e.g. trifluoroacetic acid, hydrochloric acid, or sulfuric acid,at temperatures between 0 and 100° C. A particularly suited cleavingmethod for silyl groups is based on the use of fluoride salts, e.g.tetrabutylammonium fluoride, hydrogen fluoride, or potassium fluoride,in organic solvents, such as for example diethylether, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, toluene, benzene, 1,2-dichloroethane,or dichloromethane, at temperatures between −20 and 100° C.

A benzyl, methoxybenzyl, or benzyloxycarbonyl group is advantageouslycleaved hydrogenolytically, e.g. with hydrogen in the presence of acatalyst such as palladium on carbon, palladium hydroxide, or platinumoxide in a solvent such as methanol, ethanol, ethyl acetate, or glacialacetic acid, optionally in the presence of an acid, such as hydrochloricacid, at temperatures between 0 and 100° C., preferably between 20 and60° C., and at hydrogen pressures of 1 to 7 bar, preferably 3 to 5 bar.Trimethylsilyl iodide, boron trichloride, or boron trifluoride in thepresence of a scavenger such as anisol, thioanisol, orpentamethylbenzene may be used with benzylether derivatives. Anelectron-rich benzyl residue, such as methoxybenzyl, may also be cleavedoxidatively with e.g. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) orceric ammonium nitrate (CAN) preferably in an alcoholic or aqueoussolvent at temperatures between 10 and 120° C. A 2,4-dimethoxybenzylgroup is preferably cleaved in trifluoroacetic acid in the presence of ascavenger such as anisole.

A tert-butyl or tert-butyloxycarbonyl group is preferably cleaved bytreating with an acid such as trifluoroacetic acid, sulfuric acid, orhydrochloric acid or by treating with iodotrimethylsilane, optionallyusing a solvent such as methylene chloride, 1,4-dioxane, methanol,isopropanol, water, or diethylether.

A methyl group at a tertiary amine may be cleaved by the treatment with1-chloroethyl chloroformate. Hydrobromic acid and boron tribromide areparticularly suited for the cleavage of methylethers.

The compounds of general formula I may be resolved into theirenantiomers and/or diastereomers, as mentioned before. Thus, forexample, cis/trans mixtures may be resolved into their cis and transisomers, and racemic compounds may be separated into their enantiomers.

The cis/trans mixtures may be resolved, for example, by chromatographyinto the cis and trans isomers thereof. The compounds of general formulaI which occur as racemates may be separated by methods known per se (cf.Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6,Wiley Interscience, 1971) into their optical antipodes. Diastereomericmixtures of compounds of general formula I may be resolved into theirdiastereomers by taking advantage of their different physico-chemicalproperties using methods known per se, e.g. chromatography and/orfractional crystallization; if the compounds obtained thereafter areracemates, they may be resolved into the enantiomers as mentioned above.

The racemates are preferably resolved by column chromatography on chiralphases or by crystallisation from an optically active solvent or byreacting with an optically active substance which forms salts orderivatives, such as e.g. esters or amides, with the racemic compound.Salts may be formed with enantiopure acids for basic compounds and withenantiopure bases for acidic compounds. Diastereomeric derivatives areformed with enantiopure auxiliary compounds such as e.g. acids, theiractivated derivatives, or alcohols. Separation of the diastereomericmixture of salts or derivatives thus obtained may be achieved by takingadvantage of their different physico-chemical properties, e.g.differences in solubility; the free antipodes may be released from thepure diastereomeric salts or derivatives by the action of suitableagents. Optically active acids in common use for such a purpose are e.g.the D- and L-forms of tartaric acid, dibenzoyltartaric acid,di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonicacid, glutamic acid, aspartic acid, or quinic acid. Optically activealcohols applicable as auxiliary may be, for example, (+) or (−)-mentholand optically active acyl groups in amides may be, for example, (+)- or(−)-menthyloxycarbonyl.

As mentioned above, the compounds of formula I may be converted intosalts, particularly for pharmaceutical use into the physiologicallyacceptable salts with inorganic or organic acids provided that compoundI bears a basic residue. Acids which may be used for this purposeinclude for example hydrochloric acid, hydrobromic acid, sulfuric acid,methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid,lactic acid, citric acid, tartaric acid, or maleic acid.

If the compounds of formula I contain an acidic residue like, forexample, a carboxy group, they may be converted into the salts thereofwith inorganic or organic bases, particularly for pharmaceutical useinto the physiologically acceptable salts thereof. Suitable bases forthis purpose include, for example, sodium hydroxide, potassiumhydroxide, calcium hydroxide, calcium isopropoxide, magnesium hydroxide,magnesium ethoxide, ammonium hydroxide, cyclohexylamine, ethanolamine,diethanolamine and triethanolamine, N-methyl-D-glucamine, L-lysine,L-arginine, and piperazine.

The compounds according to the invention are advantageously alsoobtainable using the methods described in the examples that follow,which may also be combined for this purpose with methods known to theskilled man from the literature.

As already mentioned, the compounds of general formula I according tothe invention and the physiologically acceptable salts thereof havevaluable pharmacological properties, particularly an inhibitory effecton the enzyme 11β-hydroxysteroid dehydrogenase (HSD) 1.

The biological properties of the new compounds may be investigated asfollows:

In vitro inhibition of 11ε-HSD 1 by test compounds was determined withHTRF (Homogeneous Time-Resolved Fluorescence) technology (cisbiointernational, France) detecting cortisol generated from cortisterone byhuman liver microsomes. Briefly, compounds were incubated for 1 hour at37° C. in Tris buffer (20 mM tris, 5 mM EDTA, pH 6.0) containing NADPH(200 μM) and cortisone (80 nM). Cortisol generated in the reaction isthen detected with a competitive immunoassay, involving two HTRFconjugates: cortisol linked to XL665 and anti-cortisol antibody labeledwith Europium cryptate. The incubation period for detection reaction wastypically 2 hours. The amount of cortisol is determined by reading thetime-resolved fluorescence of the wells (Ex 320/75 nm; Em 615/8.5 nm and665/7.5 nm). The ratio of the two emission signals is then calculated(Em665*10000/Em615). Each assay contained incubations with vehiclecontrols instead of compound as controls for non-inhibited cortisolgeneration (100% CTL; ‘high values’) and incubations with carbenoxoloneas controls for fully inhibited enzyme and cortisol background (0% CTL;‘low values’). Each assay also contained a calibration curve withcortisol to transform the fluorescent data into cortisol concentrations.Percent inhibition of each compound was determined relative to thecarbenoxolone signal.

In Table 2 the 11β-HSD 1 inhibitory activities at 1 μM concentration oftest compound, determined as described above, of the compounds listed inTable 3 are compiled, wherein 100% indicates no inhibition and a valueof zero or below zero indicates complete inhibition.

TABLE 2 Inhibitory activity on 11β-HSD 1 of the examples (=Ex.) listedin Table 3 determined as described above Ex. % CTL 1 −18 2 −27 3 −32 487 6 88 7 68 8 87 9 87 11 82 12 85 13 62 15 56 17 93 18 97 20 87 23 8329 97 30 88 31 86 32 94 33 88 34 75 35 62 36 −28 37 39 38 12 39 43 40 9842 93 43 95 44 57 45 82 46 97 47 −17 48 1 49 67 50 6 51 41 52 82 53 −5554 −56 55 31 57 63 58 68 59 95 60 63 61 94 62 −47 63 91 64 99 65 33 6677 67 85 68 66 69 93 70 19 71 41 73 90 74 69 75 92 76 76 77 47 78 49 7990 81 −9 82 5 83 −30 84 41 87 −2 88 98 90 42 91 69 93 38 94 12 95 92 9633 98 74 99 −39 100 61 101 4 102 47 103 32 104 43 105 58 106 75 107 −38108 1 109 −33 110 87 111 61 112 40 113 −23 114 −10 115 33 117 53 118 −28119 95 120 25 121 −28 122 63 123 −17 124 59 125 7 126 63 127 85 128 79129 −1 130 −47 131 −20 132 −36 133 −28 134 −5 135 −35 136 17 137 16 1384 139 21 140 −5 141 29 142 31 143 58 144 −59 145 −37 146 96 147 99 148−48 149 30 150 62 151 −44 152 5 153 −4 154 59 155 −17 156 −13 157 38 15886 159 −55 160 −26 161 −30 162 96 163 −7 164 −29 165 2 166 −33 167 −22168 6 169 −25 170 −34 171 −26 172 0 173 −46 174 −40 175 −37 176 −42 177−44 178 −22 179 −11 180 −41 181 18 x x

In view of their ability to inhibit enzyme 11β-hydroxysteroiddehydrogenase (HSD) 1, the compounds of general formula I according tothe invention and the corresponding pharmaceutically acceptable saltsthereof are theoretically suitable for the treatment and/or preventativetreatment of all those conditions or diseases which may be affected bythe inhibition of the 11β-hydroxysteroid dehydrogenase (HSD) 1 activity.Therefore, compounds according to the invention are particularlysuitable for the prevention or treatment of diseases, particularlymetabolic disorders, or conditions such as type 1 and type 2 diabetesmellitus, complications of diabetes (such as e.g. retinopathy,nephropathy or neuropathies, diabetic foot, ulcers, macroangiopathies,slow or poor wound healing), metabolic acidosis or ketosis, reactivehypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulinresistance, metabolic syndrome, dyslipidaemias of different origins,atherosclerosis and related diseases, obesity, high blood pressure,chronic heart failure, edema and hyperuricaemia. These substances mayalso be suitable for preventing beta-cell degeneration such as e.g.apoptosis or necrosis of pancreatic beta cells. The substances arepotentially also suitable for improving or restoring the functionalityof pancreatic cells, and also of increasing the number and size ofpancreatic beta cells. The compounds according to the invention may alsobe used as diuretics or antihypertensives and are suitable for theprevention and treatment of acute renal failure.

Additionally, inhibition of 11β-hydroxysteroid dehydrogenase (HSD) 1 hasbeen shown to lower intraocular pressure in subjects with ocularhypertension, therefore the compounds could be used to treat glaucoma.

In view of the role of 11β-hydroxysteroid dehydrogenase (HSD) 1 inmodulating cortisol levels for interaction with the glucocorticoidreceptor, and the known role of excess glucocorticoids in bone loss, thecompounds may have beneficial effects against osteoporosis.

Stress and/or glucocorticoids have been shown to influence cognitivefunction, and excess cortisol has been associated with brain neuronalloss or dysfunction. Treatment with an 11β-hydroxysteroid dehydrogenase(HSD) 1 inhibitor may result in amelioration or prevention of cognitiveimpairment. Such compounds may also be useful in treating anxiety ordepression.

The dynamic interaction between the immune system and the HPA(hypothalamopituitary-adrenal) axis is known, and glucocorticoids helpbalance between cell-mediated responses and humoral responses. Theimmune reaction is typically biased towards a humoral response incertain disease states, such as tuberculosis, leprosy, and psoriasis.More appropriate would be a cell-based response. An 11β-hydroxysteroiddehydrogenase (HSD) 1 inhibitor would bolster a temporal immune responsein association with immunization to ensure that a cell based responsewould be obtained, and as such could be useful in immunomodulation.

In particular, the compounds according to the invention, including thephysiologically acceptable salts thereof, are suitable for theprevention or treatment of diabetes, particularly type 1 and type 2diabetes mellitus, and/or diabetic complications.

The dosage required to achieve the corresponding activity for treatmentor prevention usually depends on the compound which is to beadministered, the patient, the nature and gravity of the illness orcondition and the method and frequency of administration and is for thepatient's doctor to decide. Expediently, the dosage may be from 1 to 100mg, preferably 1 to 30 mg, by intravenous route, and 1 to 1000 mg,preferably 1 to 100 mg, by oral route, in each case administered 1 to 4times a day. For this purpose, the compounds of formula I preparedaccording to the invention may be formulated, optionally together withother active substances, together with one or more inert conventionalcarriers and/or diluents, e.g. with corn starch, lactose, glucose,microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone,citric acid, tartaric acid, water, water/ethanol, water/glycerol,water/sorbitol, water/polyethylene glycol, propylene glycol,cetylstearyl alcohol, carboxymethylcellulose or fatty substances such ashard fat or suitable mixtures thereof, to produce conventional galenicpreparations such as plain or coated tablets, capsules, powders,suspensions or suppositories.

The compounds according to the invention may also be used in conjunctionwith other active substances, particularly for the treatment and/orprevention of the diseases and conditions mentioned above. Other activesubstances which are suitable for such combinations include for examplethose which potentiate the therapeutic effect of an 11β-hydroxysteroiddehydrogenase (HSD) 1 antagonist according to the invention with respectto one of the indications mentioned and/or which allow the dosage of an11β-hydroxysteroid dehydrogenase (HSD) 1 antagonist according to theinvention to be reduced. Therapeutic agents which are suitable for sucha combination include, for example, antidiabetic agents such asmetformin, sulfonylureas (e.g. glibenclamide, tolbutamide, glimepiride),nateglinide, repaglinide, thiazolidinediones (e.g. rosiglitazone,pioglitazone), SGLT 2 inhibitors (e.g. dapagliflozin, sergliflozin,canagliflozin, remogliflozin etabonate), PPAR-gamma-agonists (e.g. GI262570) and antagonists, PPAR-gamma/alpha modulators (e.g. KRP 297),alpha-glucosidase inhibitors (e.g. acarbose, voglibose), DPPIVinhibitors (e.g. Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin,Linagliptin), alpha2-antagonists, insulin and insulin analogues, GLP-1and GLP-1 analogues (e.g. exendin-4) or amylin. The list also includesinhibitors of protein tyrosinephosphatase 1, substances that affectderegulated glucose production in the liver, such as e.g. inhibitors ofglucose-6-phosphatase, or fructose-1,6-bisphosphatase, glycogenphosphorylase, glucagon receptor antagonists and inhibitors ofphosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvatedehydrokinase and glucokinase activators, lipid lowering agents such asfor example HMG-CoA-reductase inhibitors (e.g. simvastatin,atorvastatin), fibrates (e.g. bezafibrate, fenofibrate), nicotinic acidand the derivatives thereof, PPAR-alpha agonists, PPAR-delta agonists,ACAT inhibitors (e.g. avasimibe) or cholesterol absorption inhibitorssuch as, for example, ezetimibe, bile acid-binding substances such as,for example, cholestyramine, inhibitors of ileac bile acid transport,HDL-raising compounds such as CETP inhibitors or ABC1 regulators oractive substances for treating obesity, such as sibutramine ortetrahydrolipostatin, SDRIs, axokine, leptin, leptin mimetics,antagonists of the cannabinoid1 receptor, MCH-1 receptor antagonists,MC4 receptor agonists, NPY5 or NPY2 antagonists or β3-agonists such asSB-418790 or AD-9677 and agonists of the 5HT2c receptor.

Moreover, combinations with drugs for influencing high blood pressure,chronic heart failure or atherosclerosis such as e.g. A-II antagonistsor ACE inhibitors, ECE inhibitors, diuretics, β-blockers,Ca-antagonists, centrally acting antihypertensives, antagonists of thealpha-2-adrenergic receptor, inhibitors of neutral endopeptidase,thrombocyte aggregation inhibitors and others or combinations thereofare suitable. Examples of angiotensin II receptor antagonists arecandesartan cilexetil, potassium losartan, eprosartan mesylate,valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312,olmesartan, medoxomil, tasosartan, KT-3-671, GA-0113, RU-64276,EMD-90423, BR-9701, etc. Angiotensin II receptor antagonists arepreferably used for the treatment or prevention of high blood pressureand complications of diabetes, often combined with a diuretic such ashydrochlorothiazide.

A combination with uric acid synthesis inhibitors or uricosurics issuitable for the treatment or prevention of gout.

A combination with GABA-receptor antagonists, Na-channel blockers,topiramat, protein-kinase C inhibitors, advanced glycation end productinhibitors or aldose reductase inhibitors may be used for the treatmentor prevention of complications of diabetes.

The dosage for the combination partners mentioned above is usefully 1/5of the lowest dose normally recommended up to 1/1 of the normallyrecommended dose.

Therefore, in another aspect, this invention relates to the use of acompound according to the invention or a physiologically acceptable saltof such a compound combined with at least one of the active substancesdescribed above as a combination partner, for preparing a pharmaceuticalcomposition which is suitable for the treatment or prevention ofdiseases or conditions which can be affected by inhibiting the enzyme11β-hydroxysteroid dehydrogenase (HSD) 1. These are preferably metabolicdiseases, particularly one of the diseases or conditions listed above,most particularly diabetes or diabetic complications.

The use of the compound according to the invention, or a physiologicallyacceptable salt thereof, in combination with another active substancemay take place simultaneously or at staggered times, but particularlywithin a short space of time. If they are administered simultaneously,the two active substances are given to the patient together; while ifthey are used at staggered times the two active substances are given tothe patient within a period of less than or equal to 12 hours, butparticularly less than or equal to 6 hours.

Consequently, in another aspect, this invention relates to apharmaceutical composition which comprises a compound according to theinvention or a physiologically acceptable salt of such a compound and atleast one of the active substances described above as combinationpartners, optionally together with one or more inert carriers and/ordiluents.

Thus, for example, a pharmaceutical composition according to theinvention comprises a combination of a compound of formula I accordingto the invention or a physiologically acceptable salt of such a compoundand at least one angiotensin II receptor antagonist optionally togetherwith one or more inert carriers and/or diluents.

The compound according to the invention, or a physiologically acceptablesalt thereof, and the additional active substance to be combinedtherewith may both be present together in one formulation, for example atablet or capsule, or separately in two identical or differentformulations, for example as a so-called kit-of-parts.

The Examples that follow are intended to illustrate the presentinvention without restricting it:

LC-MS Method 1:

Column Merck Cromolith Speed ROD, RP18e, 50 × 4.6 mm Mobile A: water +0.1% HCO₂H Phase B: acetonitrile + 0.1% HCO₂H TIME (min) A % B % 0.00 9010 4.50 10 90 5.00 10 90 5.50 90 10 Flow Rate 1.5 mL/min Wavelength UV220, 230, or 254 nm

LC-MS Method 2:

Column YMC.Pack Pro C18, 50 × 4.6 mm, 3 μm Mobile A: water + 0.1% HCO₂HPhase B: acetonitrile + 0.1% HCO₂H TIME (min) A % B % 0.00 90 10 3.00 199 4.30 1 99 5.00 90 10 Flow Rate 1.2 mL/min Wavelength UV 220, 230, or254 nm

LC-MS Method 3:

Column Sunfire C18, 50 × 4.6 mm, 3.5 μm, 40° C. Mobile A: water + 0.1%F₃CCO₂H Phase B: acetonitrile + 0.1% F₃CCO₂H TIME (min) A % B % 0.00 955 2.00 0 100 2.50 0 100 2.60 95 5 Flow Rate 1.5 mL/min Wavelength UV210-500 nm

LC-MS Method 4:

Column Sunfire C18, 50 × 4.6 mm, 3.5 μm, 40° C. Mobile A: water + 0.1%F₃CCO₂H Phase B: acetonitrile + 0.08% F₃CCO₂H TIME (min) A % B % 0.00 955 2.00 0 100 3.00 0 100 3.40 95 5 Flow Rate 1.5 mL/min Wavelength UV210-500 nm

Preparation of the Starting Compounds Example I

8-Benzyl-3-(4-fluoro-phenyl)-8-aza-bicyclo[3.2.1]octan-3-ol

1-Bromo-4-fluoro-benzene (22.7 g) dissolved in diethylether (100 mL) isadded to a solution of n-butyllithium (1.7 mol/L in pentane, 86.8 mL) indiethylether (200 mL) cooled to −35° C. The combined solutions arestirred at −35-−40° C. for 1 h, before8-benzyl-8-aza-bicyclo[3.2.1]octan-3-one (22.5 g) dissolved indiethylether (150 mL) is added quickly. The solution is warmed to −10°C. within 1 h and then quenched by the addition of aqueous NH₄Clsolution. The resulting mixture is extracted with ethyl acetate, thecombined extracts are washed with brine, and then 4 M hydrochloric acidis added to the extract phase. The organic phase is separated from theaqueous phase and an oily precipitation formed after the addition. Theoily and aqueous phase are basified with 4 M aqueous NaOH solution andthe resulting mixture is extracted with ethyl acetate. The organicextracts are dried (Na₂SO₄) and the solvent is evaporated to give thetitle compound.

Yield: 21.0 g (75% of theory)

Mass spectrum (ESI⁺): m/z=312 [M+H]⁺

Example II

8-Benzyl-3-(4-fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-ene

A solution of8-benzyl-3-(4-fluoro-phenyl)-8-aza-bicyclo[3.2.1]octan-3-ol (21.0 g) inconcentrated aqueous hydrochloric acid (80 mL) is stirred at refluxtemperature for 1 h. After cooling to ambient temperature, the solutionis basified by the addition of 4 M aqueous NaOH solution. The resultingmixture is extracted with ethyl acetate and the combined extracts aredried (Na₂SO₄). The solvent is evaporated and the residue is dissolvedin ether. Methanesulfonic acid (4.3 mL) is added and the solvent isremoved under reduced pressure to give the methanesulfonic acid salt ofthe title compound.

Yield: 19.1 g (73% of theory)

Example III

endo-3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane

A mixture of the methanesulfonic acid salt of8-benzyl-3-(4-fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-ene (from ExampleII; 19.1 g) and 5% palladium on carbon (2 g) in methanol (170 mL) isshaken under hydrogen atmosphere (5 bar) at 55° C. overnight. Then, thecatalyst is separated by filtration and the filtrate is concentrated.The residue is taken up in ethyl acetate and washed with saturatedaqueous K₂CO₃ solution. The organic phase is concentrated again and theresidue is purified by chromatography on silica gel

(CH₂Cl₂/MeOH 99:1→9:1).

Yield: 3.5 g (35% of theory)

LC (method 1): t_(R)=1.82 min; Mass spectrum (ESI⁺): m/z=206 [M+H]⁺

Example IV

8-(2,3-Dihydro-benzo[1,4]dioxine-6-carbonyl)-8-aza-bicyclo[3.2.1]octan-3-one

Oxalyl chloride (10 mL) is added to2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid (14.9 g) dissolved indichloromethane (100 mL). After the addition of N,N-dimethylformamide(0.5 mL), the mixture is stirred at room temperature overnight and thenconcentrated. The residue is taken up in dichloromethane (100 mL) andadded to a mixture of nortropinone hydrochloride (10.0 g) and potassiumcarbonate (12.0 g) in dichloromethane (50 mL). Then, pyridine (18 mL) isadded and the mixture is stirred at room temperature overnight. Themixture is concentrated and the residue is taken up in dichloromethaneand washed with 1 M aqueous hydrochloric acid, 1 M aqueous NaOHsolution, and brine. After drying (Na₂SO₄), the solvent is removed underreduced pressure to yield the title compound.

Yield: 17.3 g (75% of theory)

Mass spectrum (ESI⁺): m/z=288 [M+H]⁺

Example V

Trifluoro-methanesulfonic acid8-(2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-8-aza-bicyclo[3.2.1]oct-2-en-3-ylester

Lithium bis(trimethylsilyl)amide (1 mol/L in tetrahydrofuran, 44 mL) isadded to a solution of8-(2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-8-aza-bicyclo[3.2.1]octan-3-one(11.2 g) in tetrahydrofuran (200 mL) cooled to −78° C. The solution isstirred at −78° C. for 1 h, before2-[N,N-(bistrifluoromethylsulfonyl)amino]-5-chloropyridine (17.8 g)dissolved in tetrahydrofuran (200 mL) is added dropwise over a period of1 h. The resulting solution is stirred for another 0.5 h at thistemperature and then warmed to room temperature by removing the coolingbath. Aqueous NaHCO₃ solution is added, the resulting mixture isextracted with ethyl acetate, and the combined extracts are dried(Na₂SO₄). After removal of the solvent under reduced pressure, theresidue is purified by chromatography on silica gel (cyclohexane/ethylacetate 1:0→1:1).

Yield: 11.7 g (72% of theory)

Mass spectrum (ESI⁺): m/z=420 [M+H]⁺

The following compounds are obtained analogously to Example V:

(1) Trifluoro-methanesulfonic acid8-methyl-8-aza-bicyclo[3.2.1]oct-2-en-3-yl ester

Mass spectrum (ESI⁺): m/z=272 [M+H]⁺

Alternatively, the title compound is obtained from8-methyl-8-aza-bicyclo[3.2.1]octan-3-one using potassiumbis(trimethylsilyl)amide as base andN,N-bis(trifluoromethylsulfonyl)aniline as sulfonylating agent.

(2) Trifluoro-methanesulfonic acid8-benzyl-8-aza-bicyclo[3.2.1]oct-2-en-3-yl ester

Mass spectrum (ESI⁺): m/z=348 [M+H]⁺ Alternatively, the title compoundis obtained from 8-benzyl-8-aza-bicyclo[3.2.1]octan-3-one using sodiumbis(trimethylsilyl)amide as base andN,N-bis(trifluoromethylsulfonyl)aniline as sulfonylating agent.

Example VI

(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-(3-phenyl-8-aza-bicyclo[3.2.1]oct-2-en-8-yl)-methanone

2 M aqueous Na₂CO₃ solution (1.0 mL) is added to a flask charged with astir bar, trifluoro-methanesulfonic acid8-(2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-8-aza-bicyclo[3.2.1]oct-2-en-3-ylester (0.40 g), phenylboronic acid (0.13 g), lithium chloride (87 mg),Pd(PPh₃)₄ (60 mg), water (2 mL), and 1,2-dimethoxyethane (10 mL) inargon atmosphere. The resulting mixture is stirred at reflux temperaturefor 4 h. After cooling to ambient temperature, brine is added and themixture is extracted with ethyl acetate. The combined extracts are dried(Na₂SO₄) and the solvent is removed under reduced pressure. The residueis purified by chromatography on silica gel (cyclohexane/ethyl acetate1:0→2:1).

Yield: 0.31 g (95% of theory)

Mass spectrum (ESI⁺): m/z=348 [M+H]⁺

The following compounds are obtained analogously to Example VI:

(1)3-[8-(2,3-Dihydro-benzo[1,4]dioxine-6-carbonyl)-8-aza-bicyclo[3.2.1]oct-2-en-3-yl]-4-fluoro-benzonitrile

(2)4-[8-(2,3-Dihydro-benzo[1,4]dioxine-6-carbonyl)-8-aza-bicyclo[3.2.1]oct-2-en-3-yl]-benzonitrile

Mass spectrum (ESI⁺): m/z=373 [M+H]⁺

(3)3-[8-(2,3-Dihydro-benzo[1,4]dioxine-6-carbonyl)-8-aza-bicyclo[3.2.1]oct-2-en-3-yl]-benzonitrile

Mass spectrum (ESI⁺): m/z=373 [M+H]⁺

(4)(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-(3-pyridin-4-yl-8-aza-bicyclo[3.2.1]oct-2-en-8-yl)-methanone

Mass spectrum (ESI⁺): m/z=349 [M+H]⁺

(5)(3-Biphenyl-3-yl-8-aza-bicyclo[3.2.1]oct-2-en-8-yl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone

Mass spectrum (ESI⁺): m/z=424 [M+H]⁺

(6)[3-(3-Chloro-4-fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-en-8-yl]-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone

Mass spectrum (ESI⁺): m/z=400/402 (Cl) [M+H]⁺

(7)[3-(4-Chloro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-en-8-yl]-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone

Mass spectrum (ESI⁺): m/z=382/384 (Cl) [M+H]⁺

(8)3-[8-(2,3-Dihydro-benzo[1,4]dioxine-6-carbonyl)-8-aza-bicyclo[3.2.1]oct-2-en-3-yl]-benzamide

Mass spectrum (ESI⁺): m/z=391 [M+H]⁺

(9) 3-(4-Fluoro-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]oct-2-ene

Mass spectrum (ESI⁺): m/z=218 [M+H]⁺

(10) 8-Benzyl-3-(3,4-difluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-ene

Mass spectrum (ESI⁺): m/z=312 [M+H]⁺

(11) 8-Benzyl-3-(4-methoxy-phenyl)-8-aza-bicyclo[3.2.1]oct-2-ene

(12) 8-Benzyl-3-(3-methoxy-phenyl)-8-aza-bicyclo[3.2.1]oct-2-ene

(13) 8-Benzyl-3-p-tolyl-8-aza-bicyclo[3.2.1]oct-2-ene

(14) 8-Benzyl-3-(4-isopropyl-phenyl)-8-aza-bicyclo[3.2.1]oct-2-ene

Mass spectrum (ESI⁺): m/z=318 [M+H]⁺

(15)8-Benzyl-3-(4-trifluoromethoxy-phenyl)-8-aza-bicyclo[3.2.1]oct-2-ene

Mass spectrum (ESI⁺): m/z=360 [M+H]⁺

(16) 8-Benzyl-3-(4-phenoxy-phenyl)-8-aza-bicyclo[3.2.1]oct-2-ene

(17)8-Benzyl-3-(4-trimethylsilanyl-phenyl)-8-aza-bicyclo[3.2.1]oct-2-ene

(18) 4-(8-Benzyl-8-aza-bicyclo[3.2.1]oct-2-en-3-yl)-benzoic acid methylester

(19) 8-Benzyl-3-(4-methoxymethyl-phenyl)-8-aza-bicyclo[3.2.1]oct-2-ene

(20) 8-Benzyl-3-thiophen-2-yl-8-aza-bicyclo[3.2.1]oct-2-ene

(21) 8-Benzyl-3-thiophen-3-yl-8-aza-bicyclo[3.2.1]oct-2-ene

(22) 8-Benzyl-3-pyridin-3-yl-8-aza-bicyclo[3.2.1]oct-2-ene

(23) 8-Benzyl-3-pyridin-3-yl-8-aza-bicyclo[3.2.1]oct-2-ene

(24) 8-Benzyl-3-o-tolyl-8-aza-bicyclo[3.2.1]oct-2-ene

Mass spectrum (ESI⁺): m/z=290 [M+H]⁺

(25) 8-Benzyl-3-(2-methoxy-phenyl)-8-aza-bicyclo[3.2.1]oct-2-ene

Mass spectrum (ESI⁺): m/z=306 [M+H]⁺

(26) 8-Benzyl-3-(2,6-difluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-ene

Mass spectrum (ESI⁺): m/z=312 [M+H]⁺

(27) 8-Benzyl-3-(2,4-difluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-ene

Mass spectrum (ESI⁺): m/z=312 [M+H]⁺

(28) 8-Benzyl-3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]oct-2-ene

Mass spectrum (ESI⁺): m/z=326 [M+H]⁺

(29) 8-Benzyl-3-pyrimidin-5-yl-8-aza-bicyclo[3.2.1]oct-2-ene

Mass spectrum (ESI⁺): m/z=278 [M+H]⁺

(30) 8-Benzyl-3-furan-3-yl-8-aza-bicyclo[3.2.1]oct-2-ene

Mass spectrum (ESI⁺): m/z=266 [M+H]⁺

(31) 8-Benzyl-3-pyrimidin-5-yl-8-aza-bicyclo[3.2.1]oct-2-ene

(32)[3-(4-Chloro-2-fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-en-8-yl]-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone

Mass spectrum (ESI⁺): m/z=400/402 (Cl) [M+H]⁺

(33)[3-(4-Chloro-2-fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-en-8-yl]-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone

Example VII

endo-3-(3,4-Difluoro-phenyl)-8-aza-bicyclo[3.2.1]octane

A mixture of8-benzyl-3-(3,4-difluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-ene (0.30 g)and 5% palladium on carbon (40 mg) in ethanol (5 mL) containing aceticacid (0.15 mL) is shaken under hydrogen atmosphere (5 bar) at 60° C.overnight. Then, the catalyst is separated by filtration and thefiltrate is concentrated. The residue is purified by chromatography onsilica gel (dichloromethane/methanol 99:1→9:1).

Yield: 0.16 g (74% of theory)

The following compounds are obtained analogously to Example VII:

(1) endo-3-(4-Methoxy-phenyl)-8-aza-bicyclo[3.2.1]octane

(2) endo-3-p-Tolyl-8-aza-bicyclo[3.2.1]octane

(3) endo-3-(3-Methoxy-phenyl)-8-aza-bicyclo[3.2.1]octane

(4) endo-3-(4-Trifluoromethoxy-phenyl)-8-aza-bicyclo[3.2.1]octane

(5) endo-3-(4-Isopropyl-phenyl)-8-aza-bicyclo[3.2.1]octane

(6) endo-3-(4-Phenoxy-phenyl)-8-aza-bicyclo[3.2.1]octane

(7) endo-3-(4-Trimethylsilanyl-phenyl)-8-aza-bicyclo[3.2.1]octane

(8) endo-4-(8-Aza-bicyclo[3.2.1]oct-3-yl)-benzoic acid methyl ester

(9) endo-3-(4-Methoxymethyl-phenyl)-8-aza-bicyclo[3.2.1]octane

(10) endo-3-Pyridin-3-yl-8-aza-bicyclo[3.2.1]octane

(11) endo-3-(3,5-Dimethyl-isoxazol-4-yl)-8-aza-bicyclo[3.2.1]octane

(12) endo-3-(2-Methoxy-phenyl)-8-aza-bicyclo[3.2.1]octane

Mass spectrum (ESI⁺): m/z=218 [M+H]⁺

(13) endo-3-o-Tolyl-8-aza-bicyclo[3.2.1]octane

(14) endo-3-(2,6-Difluoro-phenyl)-8-aza-bicyclo[3.2.1]octane

Mass spectrum (ESI⁺): m/z=224 [M+H]⁺

(15) endo-3-(2,4-Difluoro-phenyl)-8-aza-bicyclo[3.2.1]octane

Mass spectrum (ESI⁺): m/z=224 [M+H]⁺

(16) endo-3-Naphthalen-2-yl-8-aza-bicyclo[3.2.1]octane

Mass spectrum (ESI⁺): m/z=238 [M+H]⁺

Remark: The products obtained in analogy to the procedure describedabove mostly have high isomeric purity (endolexo in most cases >9:1).

endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(4-methoxy-3,5-dimethyl-phenyl)-methanone

2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(TBTU; 96 mg) is added to a solution of 4-methoxy-3,5-dimethyl-benzoicacid (80 mg) and ethyl-diisopropyl-amine (0.10 mL) inN,N-dimethylformamide (3 mL) at room temperature. The resulting solutionis stirred for 30 min, beforeendo-3-(4-fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane (0.13 g) is added.The solution is stirred at room temperature overnight. Then, water isadded and the resulting mixture is extracted with ethyl acetate. Thecombined extracts are dried (Na₂SO₄) and concentrated. The residue ispurified by chromatography on silica gel (caclohexane/ethyl acetate 1:1)to afford the title compound.

Yield: 70 mg (72% of theory)

LC (method 1): t_(R)=4.50 min; Mass spectrum (ESI⁺): m/z=368 [M+H]⁺

Example IX

3-Chloro-5-fluoro-4-hydroxy-benzoic acid

Sulfuryl chloride (4.7 mL) is added to a solution of3-fluoro-4-hydroxy-benzoic acid (2.97 g) in acetic acid (20 mL) stirredat 50° C. in N,N-dimethylformamide (3 mL) at room temperature. Theresulting solution is stirred for 2 h, prior to the addition of anotherportion of sulfuryl chloride (1.0 mL). The solution is stirred at 60° C.for another 1.5 h and then cooled to ambient temperature. The solutionis poured into ice-cold water and the precipitate formed is separated byfiltration, washed with ice-cold water, and dried at 50° C. to affordthe title compound as a beige solid.

Yield: 2.15 g (57% of theory)

LC (method 1): t_(R)=2.11 min; Mass spectrum (ESI⁻): m/z=189 [M−H]⁻

Preparation of the End Compounds Procedure A (Described for Example 1,Table 3)

endo-(1H-Benzoimidazol-5-yl)-[3-(4-fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(0.20 g; alternatively,2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate may be used) is added to a solution of1H-benzoimidazole-5-carboxylic acid (0.10 g) and ethyl-diisopropyl-amine(0.40 mL) in N,N-dimethylformamide (4 mL) chilled in an ice bath. Theresulting solution is stirred for 15 min, beforeendo-3-(4-fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane (0.13 g) is added.The resulting solution is warmed to room temperature and stirredovernight. Then, water is added and the resulting mixture is extractedwith ethyl acetate. The combined extracts are dried (Na₂SO₄) andconcentrated. The residue is purified by HPLC on reversed phase(H₂O/MeCN) to give the title compound.

Yield: 85 mg (39% of theory)

LC (method 2): t_(R)=2.34 min; Mass spectrum (ESI⁺): m/z=350 [M+H]⁺

Procedure B (Described for Example 133, Table 3)

(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-(3-phenyl-8-aza-bicyclo[3.2.1]oct-8-yl)-methanone,1:1 mixture of endo and exo isomer

PtO₂ (40 mg) is added to a solution of(2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3-phenyl-8-aza-bicyclo[3.2.1]oct-2-en-8-yl)-methanone(0.40 g) in methanol (5 mL). The resulting mixture is shaken in hydrogenatmosphere (1 bar) at room temperature for 6 h. Then, the mixture isfiltered and the filtrate is concentrated under reduced pressure. Theresidue is purified by chromatography on silica gel(dichloromethane/methanol 1:09:1) to give the title product as a ca. 1:1mixture of endo and exo isomer.

Yield: 0.15 g (37% of theory)

Mass spectrum (ESI⁺): m/z=350 [M+H]⁺

Procedure C (Described for Example 141, Table 3)

endo-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[3-(3-hydroxy-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

Boron tribromide (1 mol/L in dichloromethane, 0.38 mL) is added to asolution ofendo-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-[3-(3-methoxy-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone(0.15 g) in dichloromethane (3 mL) chilled in an ice bath. The resultingsolution is warmed to ca. 45° C. and stirred at this temperature for 1h. Then, another portion of boron tribromide (1 mol/L indichloromethane, 0.35 mL) is added and the solution is further stirredfor another 2 h. After cooling to room temperature, aqueous K₂CO₃solution is added, the resulting mixture is acidified with 1 Mhydrochloric acid, and extracted with ethyl acetate. The combinedextracts are dried (Na₂SO₄) and the solvent is evaporated. Depending onthe purity of the product obtained thereafter, the compound is furtherpurified by chromatography on silica gel (dichloromethane/methanol).

Yield: 0.14 g (99% of theory)

Mass spectrum (ESI⁺): m/z=366 [M+H]⁺

Procedure D (Described for Example 155, Table 3)

endo-[3-(4-Bromo-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone

Bromine (1 mol/L in dichloromethane, 0.5 mL) is added to a solution ofendo-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-[3-(4-trimethylsilyl-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone(82 mg) in dichloromethane (2 mL) chilled in an ice bath. The ice bathis removed and the solution is stirred at room temperature for 1 h.Then, aqueous solutions of Na₂S₂O₃ and NaHCO₃ are added and the mixtureis extracted with ethyl acetate. The combined extracts are dried(Na₂SO₄) and the solvent is evaporated. The residue is purified bychromatography on silica gel (dichloromethane/methanol 1:019.1).

Yield: 50 mg (52% of theory)

Mass spectrum (ESI⁺): m/z=428/430 (Br) [M+H]⁺

Procedure E (Described for Example 158, Table 3)

endo-4-[8-(2,3-Dihydro-benzo[1,4]dioxine-6-carbonyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-benzoicacid

4 M aqueous KOH solution (0.25 mL) is added to a solution ofendo-4-[8-(2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-benzoicacid methyl ester (80 mg) in methanol (3 mL). The resulting solution isstirred at room temperature for 3 h and is then acidified using 1 Mhydrochloric acid. Ethyl acetate is added and the precipitate formed isseparated by filtration and dried to give the title compound.

Yield: 37 mg (48% of theory)

Mass spectrum (ESI⁺): m/z=394 [M+H]⁺

Procedure F (Described for Example 180, Table 3)

endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(1H-indazol-5-yl)-methanone

1-Propanephosphonic acid cyclic anhydride (0.63 mL) is added to asolution of endo-3-(4-fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane(methanesulfonic acid salt, 80 mg), 1H-indazole-5-carboxylic acid (43mg), and triethylamine (0.19 mL) in tetrahydrofuran (3 mL) at roomtemperature. The resulting solution is stirred at room temperature for 4h, prior to the addition of another protion of 1-propanephosphonic acidcyclic anhydride (0.30 mL) and triethylamine (0.09 mL). The solution isfurther stirred overnight and then acidified using 1 M hydrochloricacid. The resulting mixture is extracted with ethyl acetate and thecombined extracts are dried (Na₂SO₄). The solvent is evaporated and theresidue is purified by chromatography on siilica gel(dichloromethane/methanol 1:09:1) to afford the title compound.

Yield: 30 mg (32% of theory)

LC (method 1): t_(R)=3.44 min; Mass spectrum (ESI⁺): m/z=350 [M+H]⁺

TABLE 3 Compilation of synthesized end compounds Prepared in Exampleanalogy to No. Chemical Name/Structure/Remarks ProcedureCharacterization 1endo-(1H-Benzoimidazol-5-yl)-[3-(4-fluoro-phenyl)-8-aza- A LC (method2): bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 2.34 min; MS (ESI⁺): m/z = 350 [M + H]⁺ 2endo-4-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8- A LC (method2): carbonyl]-benzamide

tR = 3.00 min; MS (ESI⁺): m/z = 353 [M + H]⁺ 3endo-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[3-(4-fluoro- A Mass spectrumphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

(ESI⁺): m/z = 368 [M + H]⁺ 4endo-(7-Difluoromethyl-5-methyl-pyrazolo[1,5- A Mass spectruma]pyrimidin-3-yl)-[3-(4-fluoro-phenyl)-8-aza- (ESI⁺):bicyclo[3.2.1]oct-8- m/z = 415 yl]-methanone [M + H]⁺

5 endo-(3,5-Dimethyl-isoxazol-4-yl)-[3-(4- A Mass spectrumfluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

(ESI⁺): m/z = 329 [M + H]⁺ 6endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- A Mass spectrum(1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl)-methanone

(ESI⁺): m/z = 340 [M + H]⁺ 7endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- A Mass spectrumthiophen-2-yl-methanone

(ESI⁺): m/z = 316 [M + H]⁺ 8endo-3-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8- A Massspectrum carbonyl]-5-methyl-4H-pyrazolo[1,5-a]pyrimidin-7-one

(ESI⁺): m/z = 381 [M + H]⁺ 9endo-5-(3-p-Tolyl-8-aza-bicyclo[3.2.1]octane-8-carbonyl)- A Massspectrum thiophene-2-carboxylic acid methyl ester

(ESI⁺): m/z = 370 [M + H]⁺ 10endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- A Mass spectrumpyridin-3-yl-methanone

(ESI⁺): m/z = 311 [M + H]⁺ 11endo-(5-tert-Butyl-2H-pyrazol-3-yl)-[3-(4-fluoro-phenyl)-8- A Massspectrum aza-bicyclo[3.2.1]oct-8-yl]-methanone

(ESI⁺): m/z = 356 [M + H]⁺ 12endo-(3,5-Difluoro-phenyl)-[3-(4-fluoro-phenyl)-8-aza- A Mass spectrumbicyclo[3.2.1]oct-8-yl]-methanone

(ESI⁺): m/z = 346 [M + H]⁺ 13endo-Thiazol-4-yl-(3-p-tolyl-8-aza-bicyclo[3.2.1]oct-8-yl)- A Massspectrum methanone

(ESI⁺): m/z = 313 [M + H]⁺ 14endo-[5-(4-Chloro-pyrazol-1-ylmethyl)-furan-2-yl]-(3-p- A Mass spectrumtolyl-8-aza-bicyclo[3.2.1]oct-8-yl)-methanone

(ESI⁺): m/z = 410/412 (Cl) [M + H]⁺ 15endo-Thiophen-2-yl-(3-p-tolyl-8-aza-bicyclo[3.2.1]oct-8- A Mass spectrumyl)-methanone

(ESI⁺): m/z = 312 [M + H]⁺ 16endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(2- A Massspectrum hydroxy-6-methyl-pyridin-3-yl)-methanone

(ESI⁺): m/z = 341 [M + H]⁺ 17 endo-Furan-2-yl-(3-p-tolyl-8-aza-bicyclo AMass spectrum [3.2.1]oct-8-yl)-methanone

(ESI⁺): m/z = 296 [M + H]⁺ 18endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- A Mass spectrumpyridin-2-yl-methanone

(ESI⁺): m/z = 311 [M + H]⁺ 19endo-(4-Amino-5-chloro-2-methoxy-phenyl)-[3-(4-fluoro- A Mass spectrumphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

(ESI⁺): m/z = 389/391 (Cl) [M + H]⁺ 20endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(1- A Massspectrum methanesulfonyl-2,3-dihydro-1H-indol-5-yl)-methanone

(ESI⁺): m/z = 429 [M + H]⁺ 21endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- A Mass spectrumpyridin-4-yl-methanone

(ESI⁺): m/z = 311 [M + H]⁺ 22endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(4- A Massspectrum methyl-thiazol-5-yl)-methanone

(ESI⁺): m/z = 331 [M + H]⁺ 23endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- A Mass spectrum(4,5,6,7-tetrahydro-1H-indazol-3-yl)-methanone

(ESI⁺): m/z = 354 [M + H]⁺ 24endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(4- A Massspectrum methyl-[1,2,3]thiadiazol-5-yl)-methanone

(ESI⁺): m/z = 332 [M + H]⁺ 25endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-[3- A Massspectrum (1H-tetrazol-5-yl)-phenyl]-methanone

(ESI⁺): m/z = 378 [M + H]⁺ 26endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(5- A Massspectrum hydroxy-pyridin-3-yl)

(ESI⁺): m/z = 327 [M + H]⁺ 27endo-(4,7-Dimethoxy-1H-indol-2-yl)-[3-(4-fluoro-phenyl)- A Mass spectrum8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

(ESI⁺): m/z = 409 [M + H]⁺ 28endo-5-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8- A Massspectrum carbonyl]-1-(2-methoxy-ethyl)-1,3-dihydro-benzoimidazol-(ESI⁺): 2-one

m/z = 424 [M + H]⁺ 29endo-7-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8- A Massspectrum carbonyl]-2-isobutyl-2,3-dihydro-isoindol-1-one

(ESI⁺): m/z = 421 [M + H]⁺ 30endo-(4,5-Dichloro-isothiazol-3-yl)-[3-(4-fluoro-phenyl)-8- A Massspectrum aza-bicyclo[3.2.1]oct-8-yl]-methanone

(ESI⁺): 385/387/389 (2Cl) [M + H]⁺ 31endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-[4- A Massspectrum (thietan-3-yloxy)-phenyl]-methanone

(ESI⁺): m/z = 398 [M + H]⁺ 32endo-[4-(Thietan-3-yloxy)-phenyl]-(3-p-tolyl-8-aza- A Mass spectrumbicyclo[3.2.1]oct-8-yl)-methanone

(ESI+): m/z = 394 [M + H]⁺ 33endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- A Mass spectrumisoquinolin-1-yl-methanone

(ESI⁺): m/z = 361 [M + H]⁺ 34endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- A Mass spectrumfuran-2-yl-methanone

(ESI⁺): m/z = 300 [M + H]⁺ 35endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- A Mass spectrumpyrazolo[1,5-a]pyrimidin-3-yl-methanone

(ESI⁺): m/z = 351 [M + H]⁺ 36endo-3-Fluoro-4-[3-(4-fluoro-phenyl)-8-aza- A Mass spectrumbicyclo[3.2.1]octane-8-carbonyl]-benzamide

(ESI⁺): m/z = 371 [M + H]⁺ 37endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- A Mass spectrumquinolin-5-yl-methanone

(ESI⁺): m/z = 361 [M + H]⁺ 38endo-(1-Ethyl-5-methyl-1H-pyrazol-4-yl)-(3-p-tolyl-8-aza- A Massspectrum bicyclo[3.2.1]oct-8-yl)-methanone

(ESI⁺): m/z = 338 [M + H]⁺ 39endo-5-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8- A Massspectrum carbonyl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one

(ESI⁺): m/z = 394 [M + H]⁺ 40endo-[3-(1,1-Dioxo-1lambda*6*-[1,2]thiazinan-2-yl)- A Mass spectrumphenyl-[3-(4-fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- (ESI⁺):methanone

m/z = 443 [M + H]⁺ 41endo-[4-(3,5-Dimethyl-pyrazol-1-yl)-phenyl]-[3-(4-fluoro- A Massspectrum phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

(ESI⁺): m/z = 404 [M + H]⁺ 42endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(5- A Massspectrum methyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-(ESI⁺): methanone

m/z = 433 [M + H]⁺ 43endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- A Mass spectrumthiazol-4-yl-methanone

(ESI⁺): m/z = 317 [M + H]⁺ 44endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- A Mass spectrum(3,4,5-trimethoxy-phenyl)-methanone

(ESI⁺): m/z = 400 [M + H]⁺ 45endo-(3-tert-Butoxy-phenyl)-[3-(4-fluoro-phenyl)-8-aza- A LC (method 4):bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 2.74 min; MS (ESI⁺): m/z = 382 [M + H]⁺ 46endo-6-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8- A LC (method4): carbonyl]-1,3-dihydro-indol-2-one

t_(R) = 2.24 min; MS (ESI⁺): m/z = 365 [M + H]⁺ 47endo-5-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8- A LC (method4): carbonyl]-1,3-dihydro-indol-2-one

t_(R) = 2.22 min; MS (ESI⁺): m/z = 365 [M + H]⁺ 48endo-(2-Amino-1H-benzoimidazol-5-yl)-[3-(4-fluoro- A LC (method 4):phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 1.86 min; MS (ESI⁺): m/z = 365 [M + H]⁺ is isolated as itstrifluoroacetic acid salt 49endo-(4-tert-Butoxy-phenyl)-[3-(4-fluoro-phenyl)-8-aza- A LC (method 4):bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 2.86 min; MS (ESI⁺): m/z = 382 [M + H]⁺ 50endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(2- A LC (method4): methyl-1H-indol-5-yl)-methanone

t_(R) = 2.86 min; MS (ESI⁺): m/z = 363 [M + H]⁺ 51endo-(1-Ethyl-1H-indol-6-yl)-[3-(4-fluoro-phenyl)-8-aza- A LC (method4): bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 2.67 min; MS (ESI⁺): m/z = 377 [M + H]⁺ is isolated as itstrifluoroacetic acid salt 52endo-(2,3-Dimethyl-1H-indol-6-yl)-[3-(4-fluoro-phenyl)-8- A LC (method4): aza-bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 2.67 min; MS (ESI⁺): m/z = 377 [M + H]⁺ is isolated as itstrifluoroacetic acid salt 53endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(1- A LC (method4): methyl-1H-indol-6-yl)-methanone

t_(R) = 2.61 min; MS (ESI⁺): m/z = 363 [M + H]⁺ is isolated as itstrifluoroacetic acid salt 54endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- A LC (method4): (1,2,3,4-tetrahydro-quinolin-6-yl)-methanone

t_(R) = 2.20 min; MS (ESI⁺): m/z = 365 [M + H]⁺ is isolated as itstrifluoroacetic acid salt 55endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(3- A LC (method3): hydroxy-4-methyl-phenyl)-methanone

t_(R) = 2.36 min; MS (ESI⁺): m/z = 340 [M + H]⁺ 56endo-N-{2-[3-(4-Fluoro-phenyl)-8-aza- A LC (method 3):bicyclo[3.2.1]octane-8-carbonyl]-phenyl}-acetamide

t_(R) = 1.73 min; MS (ESI⁺): m/z = 367 [M + H]⁺ 57endo-(2-Fluoro-phenyl)-[3-(4-fluoro-phenyl)-8-aza- A LC (method 3):bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 2.49 min; MS (ESI⁺): m/z = 328 [M + H]⁺ 58endo-1-{4-[3-(4-Fluoro-phenyl)-8-aza- A LC (method 3):bicyclo[3.2.1]octane-8-carbonyl]-phenyl}-propan-2-one

t_(R) = 2.32 min; MS (ESI⁺): m/z = 366 [M + H]⁺ 59endo-5-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8- A LC (method3): carbonyl]-1-methyl-1,3-dihydro-benzoimidazol-2-one

t_(R) = 2.08 min; MS (ESI⁺): m/z = 380 [M + H]⁺ 60endo-1-{3-[3-(4-Fluoro-phenyl)-8-aza-bi- A LC (method 3):cyclo[3.2.1]octane-8-carbonyl]-phenyl}-imidazolidin-2-one

t_(R) = 2.15 min; MS (ESI⁺): m/z = 394 [M + H]⁺ 61endo-3-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8- A LC (method3): carbonyl]-benzoic acid methyl ester

t_(R) = 2.47 min; MS (ESI⁺): m/z = 368 [M + H]⁺ 62endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- A LC (method3): (1H-indol-6-yl)-methanone

t_(R) = 2.40 min; MS (ESI⁺): m/z = 349 [M + H]⁺ is isolated as itstrifluoroacetic acid salt 63endo-2-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8- A LC (method3): carbonyl]-benzonitrile

t_(R) = 2.39 min; MS (ESI⁺): m/z = 335 [M + H]⁺ 64endo-N-{3-[3-(4-Fluoro-phenyl)-8-aza- A LC (method 3):bicyclo[3.2.1]octane-8-carbonyl]-phenyl}-acetamide

t_(R) = 2.18 min; MS (ESI⁺): m/z = 367 [M + H]⁺ 65endo-1-{4-[3-(4-Fluoro-phenyl)-8-aza- A LC (method 3):bicyclo[3.2.1]octane-8-carbonyl]-phenyl}-pyrrolidin-2-one

t_(R) = 2.27 min; MS (ESI⁺): m/z = 393 [M + H]⁺ 66endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(1- A LC (method3): methyl-1H-benzoimidazol-5-yl)-methanone

t_(R) = 1.70 min; MS (ESI⁺): m/z = 364 [M + H]⁺ is isolated as itstrifluoroacetic acid salt 67Endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- A LC (method3): (3-methanesulfonyl-phenyl)-methanone

t_(R) = 2.23 min; MS (ESI⁺): m/z = 388 [M + H]⁺ 68endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(1- A LC (method3): methyl-1H-benzotriazol-5-yl)-methanone

t_(R) = 2.21 min; MS (ESI⁺): m/z = 365 [M + H]⁺ is isolated as itstrifluoroacetic acid salt 69endo-7-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8- A LC (method3): carbonyl]-2-methyl-3H-quinazolin-4-one

t_(R) = 1.85 min; MS (ESI⁺): m/z = 392 [M + H]⁺ is isolated as itstrifluoroacetic acid salt 70endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- A LC (method3): quinoxalin-6-yl-methanone

t_(R) = 2.27 min; MS (ESI⁺): m/z = 362 [M + H]⁺ is isolated as itstrifluoroacetic acid salt 71 endo-N-{4-[3-(4-Fluoro-phenyl)-8-aza- A LC(method 3): bicyclo[3.2.1]octane-8-carbonyl]-benzyl}-acetamide

t_(R) = 2.07 min; MS (ESI⁺): m/z = 381 [M + H]⁺ 72endo-1-{2-[3-(4-Fluoro-phenyl)-8-aza- A LC (method 3):bicyclo[3.2.1]octane-8-carbonyl]-phenyl}-pyrrolidin-2-one

t_(R) = 2.20 min; MS (ESI⁺): m/z = 393 [M + H]⁺ 73endo-(1H-Benzoimidazol-4-yl)-[3-(4-fluoro-phenyl)-8-aza- A LC (method3): bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 1.72 min; MS (ESI⁺): m/z = 350 [M + H]⁺ is isolated as itstrifluoroacetic acid salt 74endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(2- A LC (method3): methyl-3H-benzoimidazol-5-yl)-methanone

tR = 1.71 min; MS (ESI⁺): m/z = 364 [M + H]⁺ is isolated as itstrifluoroacetic acid salt 75 endo-1-{3-[3-(4-Fluoro-phenyl)-8-aza- A LC(method 3): bicyclo[3.2.1]octane-8-carbonyl]-phenyl}-pyrrolidin-2-one

t_(R) = 2.28 min; MS (ESI+): m/z = 393 [M + H]+ 76endo-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-[3-(4-fluoro- A LC (method 3):phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 2.62 min; MS (ESI⁺): m/z = 390 [M + H]⁺ 77endo-(3,4-Difluoro-phenyl)-[3-(4-fluoro- A LC (method 3):phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]methanone

t_(R) = 2.52 min; MS (ESI⁺): m/z = 346 [M + H]⁺ 78endo-5-3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8- A LC (method3): carbonyl]-1-methyl-1,3-dihydro-indol-2-one

t_(R) = 2.20 min; MS (ESI⁺): m/z = 379 [M + H]⁺ 79endo-4-[3-(4-Fluoro-phenyl)-8-aza-bicyclo A LC (method 3):[3.2.1]octane-8-carbonyl]N-methyl-benzamide

t_(R) = 2.09 min; MS (ESI⁺): m/z = 367 [M + H]⁺ 80endo-3-[3-(4-Fluoro-phenyl)-8-aza-bicyclo A LC (method 3):[3.2.1]octane-8-carbonyl]-N-methyl-benzamide

t_(R) = 2.11 min; MS (ESI⁺): m/z = 367 [M + H]⁺ 81endo-4-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8- A LC (method3): carbonyl]-benzamide

t_(R) = 2.01 min; MS (ESI⁺): m/z = 353 [M + H]⁺ 82endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(3- A LC (method3): hydroxymethyl-phenyl)-methanone

t_(R) = 2.16 min; MS (ESI⁺): m/z = 340 [M + H]⁺ 83endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(3- A LC (method3): methylamino-phenyl)-methanone

t_(R) = 1.89 min; MS (ESI⁺): m/z = 393 [M + H]⁺ is isolated as itstrifluoroacetic acid salt 84endo-3-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8- A LC (method3): carbonyl]-benzamide

t_(R) = 2.03 min; MS (ESI⁺): m/z = 353 [M + H]⁺ 85endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-[4- A LC (method3): (1H-tetrazol-5-yl)-phenyl]-methanone

t_(R) = 2.15 min; MS (ESI⁺): m/z = 378 [M + H]⁺ is isolated as itstrifluoroacetic acid salt 86endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-[3- A LC (method3): (1H-tetrazol-5-yl)-phenyl]-methanone

t_(R) = 2.18 min; MS (ESI⁺): m/z = 378 [M + H]⁺ was isolated as itstrifluoroacetic acid salt 87endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(4- A LC (method3): oxazol-5-yl-phenyl)-methanone

t_(R) = 2.36 min; MS (ESI⁺): m/z = 377 [M + H]⁺ was isolated as itstrifluoroacetic acid salt 88endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-[3- A LC (method3): (5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-methanone

t_(R) = 2.50 min; MS (ESI⁺): m/z = 392 [M + H]⁺ was isolated as itstrifluoroacetic acid salt 89endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-[4- A LC (method3): (5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-methanone

t_(R) = 2.48 min; MS (ESI⁺): m/z = 392 [M + H]⁺ was isolated as itstrifluoroacetic acid salt 90endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-[3- A LC (method3): (1H-pyrazol-3-yl)-phenyl]-methanone

t_(R) = 2.24 min; MS (ESI⁺): m/z = 376 [M + H]⁺ was isolated as itstrifluoroacetic acid salt 91endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(3- A LC (method3): oxazol-5-yl-phenyl)-methanone

t_(R) = 2.37 min; MS (ESI⁺): m/z = 377 [M + H]⁺ was isolated as itstrifluoroacetic acid salt 92endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(6- A LC (method3): hydroxy-pyridin-2-yl)-methanone

t_(R) = 1.98 min; MS (ESI⁺): m/z = 327 [M + H]⁺ was isolated as itstrifluoroacetic acid salt 93endo-Benzothiazol-5-yl-[3-(4-fluoro-phenyl)-8-aza- A LC (method 3):bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 2.36 min; MS (ESI⁺): m/z = 367 [M + H]⁺ was isolated as itstrifluoroacetic acid salt 94endo-Benzothiazol-6-yl-[3-(4-fluoro-phenyl)-8-aza- A LC (method 3):bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 2.35 min; MS (ESI⁺): m/z = 367 [M + H]⁺ 95endo-7-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8- A LC (method3): carbonyl]-2,3-dihydro-isoindol-1-one

t_(R) = 2.05 min; MS (ESI⁺): m/z = 365 [M + H]⁺ 96endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- A LC (method3): phenyl-methanone

t_(R) = 2.48 min; MS (ESI⁺): m/z = 310 [M + H]⁺ 97endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- A LC (method3): pyridin-3-yl-methanone

t_(R) = 1.78 min; MS (ESI⁺): m/z = 311 [M + H]⁺ was isolated as itstrifluoroacetic acid salt 98endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- A LC (method3): pyridin-2-yl-methanone

t_(R) = 2.22 min; MS (ESI⁺): m/z = 311 [M + H]⁺ was isolated as itstrifluoroacetic acid salt 99endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-m- A LC (method3): tolyl-methanone

t_(R) = 2.58 min; MS (ESI⁺): m/z = 324 [M + H]⁺ 100endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-o- A LC (method3): tolyl-methanone

t_(R) = 2.54 min; MS (ESI⁺): m/z = 324 [M + H]⁺ 101endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-p- A LC (method3): tolyl-methanone

t_(R) = 2.58 min; MS (ESI⁺): m/z = 324 [M + H]⁺ 102endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(6- A LC (method3): hydroxy-pyridin-3-yl)-methanone

t_(R) = 1.91 min; MS (ESI⁺): m/z = 327 [M + H]⁺ was isolated as itstrifluoroacetic acid salt 103endo-(4-Fluoro-phenyl)-[3-(4-fluoro-phenyl)-8-aza- A LC (method 3):bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 2.51 min; MS (ESI⁺): m/z = 328 [M + H]⁺ 104endo-(3-Fluoro-phenyl)-[3-(4-fluoro-phenyl)-8-aza- A LC (method 3):bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 2.52 min; MS (ESI⁺): m/z = 328 [M + H]⁺ 105endo-4-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8- A LC (method3): carbonyl]-benzonitrile

t_(R) = 2.40 min; MS (ESI⁺): m/z = 335 [M + H]⁺ 106endo-3-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8- A LC (method3): carbonyl]-benzonitrile

t_(R) = 2.41 min; MS (ESI⁺): m/z = 335 [M + H]⁺ 107endo-(3,4-Dimethyl-phenyl)-[3-(4-fluoro- A LC (method 3):phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 2.66 min; MS (ESI⁺): m/z = 338 [M + H]⁺ 108endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(4- A LC (method3): methoxy-phenyl)-methanone

t _(R) = 2.47 min; MS (ESI⁺): m/z = 340 [M + H]⁺ 109endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(3- A LC (method3): methoxy-phenyl)-methanone

t_(R) = 2.48 min; MS (ESI⁺): m/z = 340 [M + H]⁺ 110endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(2- A LC (method3): methoxy-phenyl)-methanone

t_(R) = 2.45 min; MS (ESI⁺): m/z = 340 [M + H]⁺ 111endo-(2-Chloro-phenyl)-[3-(4-fluoro-phenyl)-8-aza- A LC (method 3):bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 2.55 min; MS (ESI⁺): m/z = 344/346 (Cl) [M + H]⁺ 112endo-(4-Chloro-phenyl)-[3-(4-fluoro-phenyl)-8-aza- A LC (method 3):bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 2.62 min; MS (ESI⁺): m/z = 344/346 (Cl) [M + H]⁺ 113endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- A LC (method3): (1H-indol-5-yl)-methanone

tR = 2.36 min; MS (ESI⁺): m/z = 349 [M + H]⁺ was isolated as itstrifluoroacetic acid salt 114 endo-Benzo[1,3]dioxol-5-yl-[3-(4-fluoro- ALC (method 3): phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 2.44 min; MS (ESI⁺): m/z = 354 [M + H]⁺ 115endo-N-{4-[3-(4-Fluoro-phenyl)-8-aza- A LC (method 3):bicyclo[3.2.1]octane-8-carbonyl]-phenyl}-acetamide

t_(R) = 2.16 min; MS (ESI⁺): m/z = 367 [M + H]⁺ 116endo-4-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8- A LC (method3): carbonyl]-benzoic acid methyl ester

t_(R) = 2.47 min; MS (ESI⁺): m/z = 368 [M + H]⁺ 117endo-(2,4-Dimethoxy-phenyl)-[3-(4-fluoro-phenyl)-8-aza- A LC (method 3):bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 2.45 min; MS (ESI⁺): m/z = 370 [M + H]⁺ 118endo-(3,4-Dimethoxy-phenyl)-[3-(4-fluoro-phenyl)-8-aza- A LC (method 3):bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 2.39 min; MS (ESI⁺): m/z = 370 [M + H]⁺ 119endo-4-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8- A LC (method3): carbonyl]-benzenesulfonamide

t_(R) = 2.13 min; MS (ESI⁺): m/z = 389 [M + H]⁺ 120endo-(3H-Benzotriazol-5-yl)-[3-(4-fluoro-phenyl)-8-aza- A LC (method 3):bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 2.12 min; MS (ESI⁺): m/z = 351 [M + H]⁺ was isolated as itstrifluoroacetic acid salt 121endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(4- A LC (method3): hydroxymethyl-phenyl)-methanone

t_(R) = 2.16 min; MS (ESI⁺): m/z = 340 [M + H]⁺ 122endo-(2,4-Dimethyl-phenyl)-[3-(4-fluoro-phenyl)-8-aza- A LC (method 3):bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 2.67 min; MS (ESI⁺): m/z = 338 [M + H]⁺ 123endo-(3,5-Dimethoxy-phenyl)-[3-(4-fluoro-phenyl)-8-aza- A LC (method 3):bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 2.51 min; MS (ESI⁺): m/z = 370 [M + H]⁺ 124endo-1-{3-[3-(4-Fluoro-phenyl)-8-aza- A LC (method 3):bicyclo[3.2.1]octane-8-carbonyl]-phenyl}-ethanone

t_(R) = 2.40 min; MS (ESI⁺): m/z = 352 [M + H]⁺ 125endo-(3-Chloro-phenyl)-[3-(4-fluoro-phenyl)-8-aza- A Mass spectrumbicyclo[3.2.1]oct-8-yl]-methanone

(ESI⁺): m/z = 344/346 (Cl) [M + H]⁺ 126endo-1-{2-[3-(4-Fluoro-phenyl)-8-aza- A Mass spectrumbicyclo[3.2.1]octane-8-carbonyl]-phenyl}-ethanone

(ESI⁺): m/z = 352 [M + H]⁺ 127endo-(2,3-Dimethoxy-phenyl)-[3-(4-fluoro-phenyl)-8-aza- A Mass spectrumbicyclo[3.2.1]oct-8-yl]-methanone

(ESI⁺): m/z = 370 [M + H]⁺ 128 endo-1-{4-[3-(4-Fluoro-phenyl)-8-aza- AMass spectrum bicyclo[3.2.1]octane-8-carbonyl]-phenyl}-ethanone

(ESI⁺): m/z = 352 [M + H]⁺ 129endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(3- A LC (method4): hydroxy-phenyl)-methanone

t_(R) = 2.37 min; MS (ESI⁺): m/z = 326 [M + H]⁺ 130endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(4- A LC (method4): hydroxy-phenyl)-methanone

t_(R) = 2.34 min; MS (ESI⁺): m/z = 326 [M + H]⁺ 131endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(1- A LC (method4): methyl-1H-indol-5-yl)-methanone

t_(R) = 2.65 min; MS (ESI⁺): m/z = 363 [M + H]⁺ 132endo-(2,3-Dimethyl-1H-indol-5-yl)-[3-(4-fluoro-phenyl)-8- A LC (method4): aza-bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 2.68 min; MS (ESI⁺): m/z = 377 [M + H]⁺ 133(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-(3-phenyl-8-aza- B Mass spectrumbicyclo[3.2.1]oct-8-yl)-methanone

(ESI⁺): m/z = 350 [M + H]⁺ 1:1 mixture of endo and exo isomer 134endo-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[3-(4-methoxy- A Mass spectrumphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

or B (ESI⁺): m/z = 380 [M + H]⁺ using procedure B requires separationfrom the exo isomer by HPLC on chiral phase 135exo-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[3-(4-methoxy- B Mass spectrumphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

(ESI⁺): m/z = 380 [M + H]⁺ was separated from the endo isomer by HPLC onchiral phase 136endo-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[3-(4-isopropyl- A Massspectrum phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

(ESI⁺): m/z = 392 [M + H]⁺ 137endo-[3-(3,4-Difluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8- A Mass spectrumyl]-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone

(ESI⁺): m/z = 392 [M + H]⁺ 138endo-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-(3-p-tolyl-8-aza- A Massspectrum bicyclo[3.2.1]oct-8-yl)-methanone

(ESI⁺): m/z = 364 [M + H]⁺ 139endo-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[3-(3-methoxy- A Mass spectrumphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

(ESI⁺): m/z = 380 [M + H]⁺ 140endo-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[3-(4- A Mass spectrumtrifluoromethoxy-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- (ESI⁺):methanone

m/z =434 [M + H]⁺ 141endo-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[3-(3-hydroxy- C Mass spectrumphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

(ESI⁺): m/z = 366 [M + H]⁺ 142endo-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[3-(4-hydroxy- C Mass spectrumphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

(ESI⁺): m/z = 366 [M + H]⁺ 143endo-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[3-(4-trimethyl- A Massspectrum silyl-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

(ESI⁺): m/z =422 [M + H]⁺ 144[3-(4-Chloro-2-fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- B Massspectrum (2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone

(ESI⁺): m/z =402/404 (Cl) [M + H]⁺ ca. 1.3:1 mixture of exo and endoisomer 145 (2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[3-(2-fluoro-phenyl)-8- BMass spectrum aza-bicyclo[3.2.1]oct-8-yl]-methanone

(ESI⁺): m/z = 368 [M + H]⁺ ca. 1.1:1 mixture of exo and endo isomer, thecompound was obtained as side product from the preparation of example144 146 [3-(4-Aminomethyl-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- B Massspectrum (2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone

(ESI⁺): m/z = 368 [M + H]⁺ ca. 2.5:1 mixture of exo and endo isomer, thecompound was obtained from 4-[8-(2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-8-aza-bicyclo[3.2.1]oct-2-en-3-yl]-benzonitrile using procedure B 147exo-[3-(3-Aminomethyl-phenyl)-8-aza-bicyclo[3.2.1]oct-8- B Mass spectrumyl]-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone

(ESI⁺): m/z = 379 [M + H]⁺ the compound was obtained from3-[8-(2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-8-aza-bicyclo[3.2.1]oct-2-en-3-yl]-benzonitrile using procedure B 148[3-(3-Chloro-4-fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- B Massspectrum (2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone

(ESI⁺): m/z =402/404 (Cl) [M + H]⁺ ca. 1.7:1 mixture of exo and endoisomer 149 3-[8-(2,3-Dihydro-benzo[1,4]dioxine-6-carbonyl)-8-aza- B Massspectrum bicyclo[3.2.1]oct-3-yl]-benzamide

(ESI⁺): m/z = 393 [M + H]⁺ ca. 2.4:1 mixture of exo and endo isomer 150(3-Biphenyl-3-yl-8-aza-bicyclo[3.2.1]oct-8-yl)-(2,3-dihydro- B Massspectrum benzo[1,4]dioxin-6-yl)-methanone

(ESI⁺): m/z =426 [M + H]⁺ ca. 1:1 mixture of exo and endo isomer 151[3-(4-Chloro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(2,3- B Mass spectrumdihydro-benzo[1,4]dioxin-6-yl)-methanone

(ESI⁺): m/z = 384/386 (Cl) [M + H]⁺ ca. 2.6:1 mixture of exo and endoisomer 152 endo-(2,3-Dihydro-benzo[1 ,4]dioxin-6-yl)-[3-(4-phenoxy- AMass spectrum phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

(ESI⁺): m/z =442 [M + H]⁺ 153endo-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-(3-pyridin-3-yl- A Massspectrum 8-aza-bicyclo[3.2.1]oct-8-yl)-methanone

(ESI⁺): m/z = 351 [M + H]⁺ 154endo-448-(2,3-Dihydro-enzo[1,4]dioxine-6-carbonyl)-8- A Mass spectrumaza-bicyclo[3.2.1]oct-3-yl]-benzoic acid methyl ester

(ESI⁺): m/z = 408 [M + H]⁺ 155endo-[3-(4-Bromo-phenyl)-8-aza-icyclo[3.2.1]oct-8-yl]- D Mass spectrum(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone

(ESI⁺): m/z = 428/430 (Br) [M + H]⁺ 156endo-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[3-(2-methoxy- A Mass spectrumphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

(ESI⁺): m/z = 380 [M + H]⁺ 157endo-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-(3-naphthalen- A Mass spectrum2-yl-8-aza-bicyclo[3.2.1]oct-8-yl)-methanone

(ESI⁺): m/z = 400 [M + H]⁺ 158endo-4-[8-(2,3-Dihydro-enzo[1,4]dioxine-6-carbonyl)-8- E Mass spectrumaza-bicyclo[3.2.1]oct-3-yl]-benzoic acid

(ESI⁺): m/z =408 [M + H]⁺ 159endo-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[3-(2-hydroxy- C Mass spectrumphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

(ESI⁺): m/z = 366 [M + H]⁺ 160endo-[3-(2,4-Difluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8- A Mass spectrumyl]-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone

(ESI⁺): m/z = 386 [M + H]⁺ 161endo-[3-(2,6-Difluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8- A Mass spectrumyl]-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone

(ESI⁺): m/z = 386 [M + H]⁺ 162endo-(7-Difluoromethyl-5-methyl-[1,2,4]triazolo[1,5- A Mass spectruma]pyrimidin-2-yl)-[3-(4-fluoro-phenyl)-8-aza- (ESI⁺):bicyclo[3.2.1]oct-8-yl]-methanone

m/z =416 [M + H]⁺ 163 endo-(3,5-Dichloro-4-hydroxy-phenyl)-[3-(4-fluoro-A LC (method 1): phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 4.07 min; MS (ESI⁺): m/z = 394/396/398 (2Cl) [M + H]⁺ 164endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(4- C LC (method1): hydroxy-3,5-dimethyl-phenyl)-methanone

t_(R) = 3.91 min; MS (ESI⁺): m/z = 354 [M + H]⁺ 165endo-(3-Chloro-4-methoxy-phenyl)-[3-(4-fluoro-phenyl)-8- A LC (method1): aza-bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 4.34 min; MS (ESI⁺): m/z = 374/376 (Cl) [M + H]⁺ 166endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(4- A LC (method1): hydroxy-3-methyl-phenyl)-methanone

t_(R) = 3.71 min; MS (ESI⁺): m/z = 340 [M + H]⁺ 167endo-(3-Chloro-4-hydroxy-phenyl)-[3-(4-fluoro-phenyl)-8- C LC (method1): aza-bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 3.79 min; MS (ESI⁺): m/z = 360/362 (Cl) [M + H]⁺ 168endo-(3,5-Difluoro-4-methoxy-phenyl)-[3-(4-fluoro- A LC (method 1):phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 4.01 min; MS (ESI⁺): m/z = 376 [M + H]⁺ 169endo-(3-Fluoro-4-hydroxy-phenyl)-[3-(4-fluoro-phenyl)-8- A LC (method1): aza-bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 2.73 min; MS (ESI⁺): m/z = 344 [M + H]⁺ 170endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(4- A LC (method1): methoxy-3-methyl-phenyl)-methanone

t_(R) = 4.43 min; MS (ESI⁺): m/z = 354 [M + H]⁺ 171endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(4- A LC (method1): hydroxy-3-methoxy-phenyl)-methanone

t_(R) = 3.54 min; MS (ESI⁺): m/z = 356 [M + H]⁺ 172endo-(3,5-Difluoro-4-hydroxy-phenyl)-[3-(4-fluoro-phenyl)- C LC (method1): 8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 3.72 min; MS (ESI⁺): m/z = 362 [M + H]⁺ 173endo-(4-Amino-3-chloro-phenyl)-[3-(4-fluoro-phenyl)-8- A LC (method 1):aza-bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 3.93 min; MS (ESI⁺): m/z = 359/361 (Cl) [M + H]⁺ 174endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(4- A LC (method1): hydroxy-3-trifluoromethyl-phenyl)-methanone

t_(R) = 3.99 min; MS (ESI⁺): m/z = 394 [M + H]⁺ 175endo-(3-Chloro-4-hydroxy-5-methoxy-phenyl)-[3-(4- A LC (method 1):fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 3.88 min; MS (ESI⁺): m/z = 390/392 (Cl) [M + H]⁺ 176endo-(4-Amino-3-fluoro-phenyl)-[3-(4-fluoro-phenyl)-8- A LC (method 1):aza-bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 3.70 min; MS (ESI⁺): m/z = 343 [M + H]⁺ 177endo-(4-Amino-phenyl)-[3-(4-fluoro-phenyl)-8-aza- A LC (method 1):bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 3.67 min; MS (ESI⁺): m/z = 325 [M + H]⁺ 178endo-(4-Amino-3,5-dichloro-phenyl)-[3-(4-fluoro-phenyl)- A LC (method1): 8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 4.29 min; MS (ESI⁺): m/z = 393/395/ 397 (2 Cl) [M + H]⁺ 179endo-(3-Chloro-5-fluoro-4-hydroxy-phenyl)-[3-(4-fluoro- A LC (method 1):phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-methanone

t_(R) = 3.87 min; MS (ESI⁺): m/z = 376/378 (Cl) [M + H]⁺ 180endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]- F LC (method1): (1H-indazol-5-yl)-methanone

t_(R) = 3.44 min; MS (ESI⁺): m/z = 350 [M + H]⁺ 181endo-[3-(4-Fluoro-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-(4- F LC (method1): hydroxy-3,5-dimethoxy-phenyl)-methanone

t_(R) = 3.50 min; MS (ESI⁺): m/z = 386 [M + H]⁺

Some examples of formulations will now be described in which the term“active substance” denotes one or more compounds according to theinvention, including the salts thereof. In the case of one of thecombinations with one or additional active substances as describedpreviously, the term “active substance” also includes the additionalactive substances.

Example A Tablets Containing 100 mg of Active Substance Composition:

1 tablet contains: active substance 100.0 mg lactose  80.0 mg cornstarch  34.0 mg polyvinylpyrrolidone  4.0 mg magnesium stearate  2.0 mg220.0 mg

Method of Preparation:

The active substance, lactose and starch are mixed together anduniformly moistened with an aqueous solution of thepolyvinylpyrrolidone. After the moist composition has been screened (2.0mm mesh size) and dried in a rack-type drier at 50° C. it is screenedagain (1.5 mm mesh size) and the lubricant is added. The finishedmixture is compressed to form tablets.

-   -   Weight of tablet: 220 mg    -   Diameter: 10 mm, biplanar, facetted on both sides and notched on        one side.

Example B Tablets Containing 150 mg of Active Substance Composition:

1 tablet contains: active substance 150.0 mg  powdered lactose 89.0 mgcorn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0mg magnesium stearate  1.0 mg 300.0 mg 

Preparation:

The active substance mixed with lactose, corn starch and silica ismoistened with a 20% aqueous polyvinylpyrrolidone solution and passedthrough a screen with a mesh size of 1.5 mm. The granules, dried at 45°C., are passed through the same screen again and mixed with thespecified amount of magnesium stearate. Tablets are pressed from themixture.

-   -   Weight of tablet: 300 mg    -   die: 10 mm, flat

Example C Hard Gelatine Capsules Containing 150 mg of Active SubstanceComposition:

1 capsule contains: active substance 150.0 mg corn starch (dried)approx. 180.0 mg lactose (powdered) approx. 87.0 mg magnesium stearate3.0 mg approx. 420.0 mg

Preparation:

The active substance is mixed with the excipients, passed through ascreen with a mesh size of 0.75 mm and homogeneously mixed using asuitable apparatus. The finished mixture is packed into size 1 hardgelatine capsules.

-   -   Capsule filling: approx. 320 mg    -   Capsule shell: size 1 hard gelatine capsule.

Example D Suppositories Containing 150 mg of Active SubstanceComposition:

1 suppository contains: active substance 150.0 mg polyethyleneglycol1500 550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitanmonostearate 840.0 mg 2,000.0 mg  

Preparation:

After the suppository mass has been melted the active substance ishomogeneously distributed therein and the melt is poured into chilledmoulds.

Example E Ampoules Containing 10 mg Active Substance Composition:

active substance  10.0 mg 0.01N hydrochloric acid q.s. double-distilledwater ad 2.0 mL

Preparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 2mL ampoules.

Example F Ampoules Containing 50 mg of Active Substance Composition:

active substance  50.0 mg 0.01N hydrochloric acid q.s. double-distilledwater ad 10.0 mL

Preparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 10mL ampoules.

1. A compound of formula (I)

wherein R¹ denotes phenyl, naphthyl pyrrolyl, furanyl, thienyl,pyridinyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl,isoquinolinyl, pyrrolyl, imidazolyl, furanyl, thienyl, pyridinyl, ineach of which one or two CH groups are replaced by N, indolyl,benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, in each ofwhich 1 to 3 CH groups are replaced by N, or pyrazolopyrimidinyl,triazolopyrimidinyl, while in the above-mentioned N-heteroaromaticgroups one or two —N═CH— groups are optionally replaced by —NH—CO—and/or —N(C₁₋₄-alkyl)-CO—, and while the above-mentioned polycyclicaromatic and heteroaromatic groups may be partially saturated, though,retaining an aromatic or heteroaromatic substructure that is attached tothe carbonyl group in formula I, where in the partially saturated ringsone or two CH₂ groups are optionally replaced independently by oxygen,sulfur, NH, N(C₁₋₄-alkyl), carbonyl, or sulfonyl, wherein theabove-mentioned aromatic, heteroaromatic, partially saturated aromaticand heteroaromatic groups are optionally substituted with one or more,preferably one to four, substituents R⁴, and wherein 2 adjacent C-atomsof each of said rings are optionally substituted with R⁵ and R⁶, andwherein all heteroaromatic rings are attached to the carbonyl group informula I via a carbon atom, R² denotes phenyl, naphthyl, pyrrolyl,furanyl, thienyl, pyridinyl, indolyl, benzofuranyl, benzothiophenyl,quinolinyl, isoquinolinyl, pyrrolyl, imidazolyl, furanyl, thienyl,pyridinyl, in each of which one or two CH groups are replaced by N,indolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, ineach of which 1 to 3 CH groups are replaced by N, while theabove-mentioned aromatic and heteroaromatic groups are optionallysubstituted with one or more, preferably one to four, substituents R⁷,wherein all heteroaromatic rings are attached to the nortropane skeletonin formula I via a carbon atom, R⁴ independently of each other denoteshalogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, hydroxy, C₁₋₄-alkyloxy,nitro, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino, pyrrolidin-1-yl,2-oxo-pyrrolidin-1-yl, piperidin-1-yl, 2-oxo-piperidin-1-yl,morpholin-4-yl, 3-oxo-morpholin-4-yl, piperazin-1-yl,2-oxo-piperazin-1-yl, 3-oxo-piperazin-1-yl,4-(C₁₋₃-alkyl)-piperazin-1-yl, 4-(C₁₋₄-alkylcarbonyl)-piperazin-1-yl,4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,4-(C₁₋₄-alkyl-oxycarbonyl)-piperazin-1-yl, 4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl, 2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl, C₁₋₃-alkyl-carbonylamino,(het)aryl-carbonylamino, (het)aryl-C₁₋₃-alkyl-carbonyl-amino,C₁₋₃-alkyloxy-carbonylamino, aminocarbonylamino,C₁₋₃-alkyl-amino-carbonylamino, di-(C₁₋₃-alkyl)aminocarbonylamino,pyrrolidin-1-yl-carbonyl amino, piperidin-1-yl-carbonyl-amino,morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino,4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl amino, C₁₋₃-alkyl-sulfonyl amino,aminosulfonylamino, C₁₋₃-alkyl amino-sulfonylamino,di-(C₁₋₃-alkyl)amino-sulfonylamino, pyrrolidin-1-yl-sulfonylamino,piperidin-1-yl-sulfonylamino, morpholin-4-yl-sulfonylamino,piperazin-1-yl-sulfonylamino,4-(C₁₋₃-alkyl)-piperazin-1-yl-sulfonylamino,(C₁₋₃-alkyloxy-carbonyl-amino)carbonylamino, (het)arylsulfonylamino,(het)aryl-C₁₋₃-alkyl-sulfonylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-carbonylamino, N—(C₁₋₃-alkyl)-(het)arylcarbonylamino, N—(C₁₋₃-alkyl)-(het) aryl-C₁₋₃-alkyl-carbonylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyloxy-carbonylamino,N-(aminocarbonyl)-C₁₋₃-alkylamino,N—(C₁₋₃-alkyl-aminocarbonyl)-C₁₋₃-alkylamino,N-[di-(C₁₋₃-alkyl)aminocarbonyl]-C₁₋₃-alkylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-sulfonylamino,N—(C₁₋₃-alkyl)-(het)arylsulfonylamino,N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkyl-sulfonylamino,oxo-imidazolidin-1-yl, 2,4-dioxo-imidazolidin-1-yl,2,5-dioxo-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl, wherein thenitrogen atom in position 3 of the aforementioned groups is optionallysubstituted with methyl or ethyl, 1,1-dioxothiazinanyl, cyano, carboxy,C₁₋₃-alkyloxy-carbonyl, aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, pyrrolidin-1-yl-carbonyl,piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl,piperazin-1-yl-carbonyl, 4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl,(het)aryl-aminocarbonyl, N—(C₁₋₃-alkyl)-(het)arylaminocarbonyl,(het)aryl-C₁₋₃-alkylamino-carbonyl,N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkylaminocarbonyl, C₁₋₄-alkyl-carbonyl,(het)aryl-carbonyl, C₁₋₃-alkylcarbonyl-C₁₋₃-alkyl, carboxy-C₁₋₃-alkyl,C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyl, cyano-C₁₋₃-alkyl,aminocarbonyl-C₁₋₃-alkyl, C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl,pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl, piperidin-1-yl-carbonyl-C₁₋₃-alkyl,morpholin-4-yl-carbonyl-C₁₋₃-alkyl, piperazin-1-yl-carbonyl-C₁₋₃-alkyl,4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl-C₁₋₃-alkyl,carboxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyloxy,cyano-C₁₋₃-alkyloxy, aminocarbonyl-C₁₋₃-alkyloxy,C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyloxy,di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy,pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl-oxy,piperidin-1-yl-carbonyl-C₁₋₃-alkyloxy,morpholin-4-yl-carbonyl-C₁₋₃-alkyl-oxy,piperazin-1-yl-carbonyl-C₁₋₃-alkyloxy,4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl-C₁₋₃-alkyloxy,hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,pyrrolidin-1-yl-C₁₋₃-alkyl, 2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl,piperidin-1-yl-C₁₋₃-alkyl, 2-oxo-piperidin-1-yl-C₁₋₃-alkyl,morpholin-4-yl-C₁₋₃-alkyl, 3-oxo-morpholin-4-yl-C₁₋₃-alkyl,piperazin-1-yl-C₁₋₃-alkyl, 2-oxo-piperazin-1-yl-C₁₋₃-alkyl,3-oxo-piperazin-1-yl-C₁₋₃-alkyl,4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl, arylcarbonylamino-C₁₋₃-alkyl,hydroxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-C₁₋₃-alkyloxy,C₁₋₃-alkylsulfanyl-C₁₋₃-alkyloxy, C₁₋₃-alkylsulfinyl-C₁₋₃-alkyloxy,C₁₋₃-alkylsulfonyl-C₁₋₃-alkyloxy, amino-C₁₋₃-alkyloxy,C₁₋₃-alkylamino-C₁₋₃-alkyloxy, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyloxy,pyrrolidin-1-yl-C₁₋₃-alkyloxy, 2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyloxy,piperidin-1-yl-C₁₋₃-alkyloxy, 2-oxo-piperidin-1-yl-C₁₋₃-alkyloxy,morpholin-4-yl-C₁₋₃-alkyloxy, 3-oxo-morpholin-4-yl-C₁₋₃-alkyloxy,piperazin-1-yl-C₁₋₃-alkyloxy, 2-oxo-piperazin-1-yl-C₁₋₃-alkyloxy,3-oxo-piperazin-1-yl-C₁₋₃-alkyloxy,4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyloxy,2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyloxy,3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyloxy, C₁₋₃-alkylsulfanyl,C₁₋₃-alkylsulfinyl, C₁₋₃-alkylsulfonyl, C₁₋₃-alkylsulfonyloxy,(het)arylsulfonyl, (het)arylsulfonyloxy, trifluoromethylsulfanyl,trifluoromethylsulfinyl, trifluoromethylsulfonyl, aminosulfonyl,C₁₋₃-alkyl-aminosulfonyl, di-(C₁₋₃-alkyl)-aminosulfonyl,pyrrolidin-1-yl-sulfonyl, piperidin-1-yl-sulfonyl,morpholin-4-yl-sulfonyl, piperazin-1-yl-sulfonyl,4-(C₁₋₃-alkyl)-piperazin-1-yl-sulfonyl, difluoromethyl, trifluoromethyl,difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoro-1-hydroxyethyl,2,2,2-trifluoro-1-hydroxy-1-methylethyl,2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyloxy, C₃₋₆-cycloalkyl-C₁₋₃-alkyl,C₃₋₆-cycloalkyl-C₁₋₃-alkyloxy, (het)aryl, (het)aryloxy,(het)aryl-C₁₋₃-alkyl, (het)aryl-C₁₋₃-alkyloxy, (het)aryloxy-C₁₋₃-alkyl,or tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,tetrahydropyran-4-yloxy, tetrahydro-furanyl-C₁₋₃-alkyloxy,tetrahydropyranyl-C₁₋₃-alkyloxy, thietan-3-yloxy, while theabove-mentioned C_(3-n)-cycloalkyl and C_(3-n)-cycloheteroalkyl groupsare optionally substituted with one or two groups selected fromfluorine, C₁₋₃-alkyl, C₁₋₃-alkoxy, C₁₋₃-alkoxy-C₁₋₃-alkyl, or hydroxy,and wherein one CH₂ group is optionally replaced by CO or SO₂, and R⁵and R⁶ are linked to each other and bound to adjacent carbon atoms andform together a methylenedioxy, ethylenedioxy, or C₃₋₅-alkylene bridginggroup, which is optionally mono- or disubstituted with fluorine and/ormethyl; or R⁵ and R⁶ may form combined with the carbon atoms they areattached to a benzo, pyrido, pyrimido, pyrrolo, furano, thieno,pyrazolo, imidazo, oxazolo, thiazolo, isoxazolo, or isothiazolo ring,wherein each of said rings is optionally substituted with one or more,preferably one to four, substituents independently of each otherselected from halogen, C₁₋₃-alkyl, trifluoromethyl, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino, C₁₋₃-alkylcarbonylamino, hydroxy,cyano, carboxy, C₁₋₃-alkyloxycarbonyl and C₁₋₃-alkyloxy, R⁷independently of each other denotes halogen, nitro, cyano, hydroxy,C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyloxy, tetrahydrofuran-3-yloxy,tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy,tetrahydrofuranyl-C₁₋₃-alkyloxy, tetrahydropyranyl-C₁₋₃-alkyloxy,(het)aryl, (het)aryloxy, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₁₋₄-alkyloxy, where in each group optionally one CH₂ group is replacedby carbonyl or sulfonyl and each of which is optionally mono- orpolyfluorinated and optionally mono- or disubstituted with hydroxy,chlorine, C₁₋₃-alkyloxy, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, piperidin-1-yl,2-oxo-piperidin-1-yl, morpholin-4-yl, 3-oxo-morpholin-4-yl,piperazin-1-yl, 2-oxo-piperazin-1-yl, 3-oxo-piperazin-1-yl,4-(C₁₋₃-alkyl)-piperazin-1-yl, 2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl, carboxy, C₁₋₃-alkyloxy-carbonyl,cyano, aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, pyrrolidin-1-yl-carbonyl,piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl,piperazin-1-yl-carbonyl, 4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl,C₁₋₃-alkyl-carbonylamino, arylcarbonylamino, C₁₋₃-alkylsulfanyl,C₁₋₃-alkylsulfinyl, C₁₋₃-alkylsulfonyl, C₃₋₆-cycloalkyl, (het)aryl, or(het)aryloxy; amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino,pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, piperidin-1-yl,2-oxo-piperidin-1-yl, morpholin-4-yl, 3-oxo-morpholin-4-yl,piperazin-1-yl, 2-oxo-piperazin-1-yl, 3-oxo-piperazin-1-yl,4-(C₁₋₃-alkyl)-piperazin-1-yl, 4-(C₁₋₄-alkylcarbonyl)-piperazin-1-yl,4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,4-(C₁₋₄-alkyloxycarbonyl)-piperazin-1-yl, 4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl, 2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl, C₁₋₄-alkyl-carbonylamino,(het)aryl-carbonylamino, (het)aryl-C₁₋₃-alkyl-carbonyl-amino,C₁₋₃-alkyloxy-carbonylamino, aminocarbonylamino,C₁₋₃-alkyl-amino-carbonylamino, di-(C₁₋₃-alkyl)aminocarbonylamino,pyrrolidin-1-yl-carbonyl-amino, piperidin-1-yl-carbonylamino,morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino,4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonylamino, C₁₋₃-alkyl-sulfonylamino,aminosulfonylamino, C₁₋₃-alkylamino-sulfonylamino,di-(C₁₋₃-alkyl)amino-sulfonylamino, pyrrolidin-1-yl-sulfonylamino,piperidin-1-yl-sulfonylamino, morpholin-4-yl-sulfonylamino,piperazin-1-yl-sulfonylamino,4-(C₁₋₃-alkyl)-piperazin-1-yl-sulfonylamino,(C₁₋₃-alkyloxy-carbonyl-amino)carbonylamino, (het)arylsulfonylamino,(het)aryl-C₁₋₃-alkyl-sulfonylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-carbonylamino, N—(C₁₋₃-alkyl)-(het)arylcarbonylamino, N—(C₁₋₃-alkyl)-(het) aryl-C₁₋₃-alkyl-carbonylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyloxy-carbonylamino,N-(aminocarbonyl)-C₁₋₃-alkylamino,N—(C₁₋₃-alkyl-aminocarbonyl)-C₁₋₃-alkylamino,N-[di-(C₁₋₃-alkyl)aminocarbonyl]-C₁₋₃-alkylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-sulfonylamino,N—(C₁₋₃-alkyl)-(het)arylsulfonylamino,N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkyl-sulfonylamino, carboxy,C₁₋₃-alkyloxy-carbonyl, aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, pyrrolidin-1-yl-carbonyl,piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl,piperazin-1-yl-carbonyl, 4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl, (het)aryl-aminocarbonyl, N—(C₁₋₃-alkyl)-(het)arylaminocarbonyl,(het)aryl-C₁₋₃-alkylamino-carbonyl,N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkylaminocarbonyl, C₁₋₃-alkylsulfanyl,C₁₋₃-alkysulfinyl, (het)arylsulfonyl, trifluoromethylsulfanyl,trifluoromethylsulfinyl, aminosulfonyl, C₁₋₃-alkyl-aminosulfonyl,di-(C₁₋₃-alkyl)-aminosulfonyl, pyrrolidin-1-yl-sulfonyl,piperidin-1-yl-sulfonyl, morpholin-4-yl-sulfonyl,piperazin-1-yl-sulfonyl, 4-(C₁₋₃-alkyl)-piperazin-1-yl-sulfonyl, whereinthe above-mentioned C_(3-n)-cycloalkyl and C_(3-n)-cycloheteroalkylgroups are optionally substituted with one or two groups selected fromfluorine, C₁₋₃-alkyl, C₁₋₃-alkoxy, C₁₋₃-alkoxy-C₁₋₃-alkyl, or hydroxy,and wherein one CH₂ group is optionally replaced by CO or SO₂, and R¹¹independently of each other denotes halogen, C₁₋₄-alkyl, difluoromethyl,trifluoromethyl, cyano, nitro, amino, C₁₋₃-alkylcarbonylamino,C₁₋₃-alkylsulfonylamino, carboxy, C₁₋₄-alkyloxycarbonyl, aminocarbonyl,C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl, aminosulfonyl,C₁₋₃-alkylaminosulfonyl, di-(C₁₋₃-alkyl)-aminosulfonyl,C₁₋₃-alkylsulfanyl, C₁₋₃-alkylsulfinyl, C₁₋₃-alkylsulfonyl, hydroxy,C₁₋₃-alkyloxy, difluoromethoxy, trifluoromethoxy, phenyl, while theabove-mentioned (het)aryl is phenyl, naphthyl, pyrrolyl, furanyl,thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl,isoquinolinyl, or pyrrolyl, furanyl, thienyl, imidazolyl, pyridyl inwhich 1 or 2 CH are replaced by N, or indolyl, benzofuranyl,benzothiophenyl, quinolinyl, isoquinolinyl in which 1 to 3 CH arereplaced by N, or a ring selected from the group consisting of1,2-dihydro-2-oxo-pyridinyl, 1,4-dihydro-4-oxo-pyridinyl,2,3-dihydro-3-oxo-pyridazinyl, 1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl,1,2-dihydro-2-oxo-pyrimidinyl, 3,4-dihydro-4-oxo-pyrimidinyl,1,2,3,4-tetrahydro-2,4-dioxo-pyrimidinyl, 1,2-dihydro-2-oxo-pyrazinyl,1,2,3,4-tetrahydro-2,3-dioxo-pyrazinyl, 2,3-di-hydro-2-oxo-indolyl,2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxo-1H-benzimidazolyl,2,3-dihydro-2-oxo-benzoxazolyl, 1,2-dihydro-2-oxo-quinolinyl,1,4-dihydro-4-oxo-quinolinyl, 1,2-dihydro-1-oxo-isoquinolinyl,1,4-dihydro-4-oxo-cinnolinyl, 1,2-dihydro-2-oxo-quinazolinyl,1,4-dihydro-4-oxo-quinazolinyl,1,2,3,4-tetrahydro-2,4-dioxo-quinazolinyl,1,2-dihydro-2-oxoquinoxalinyl, 1,2,3,4-tetrahydro-3-oxo-quinoxalinyl,1,2,3,4-tetrahydro-2,3-dioxo-quinoxalinyl,1,2-dihydro-1-oxo-phthalazinyl,1,2,3,4-tetrahydro-1,4-dioxo-phthalazinyl, chromanyl, coumarinyl,2,3-dihydro-benzo[1,4]dioxinyl and3,4-dihydro-3-oxo-2H-benzo[1,4]oxazinyl, wherein each (het)aryl isoptionally substituted with 1, 2, or 3 R¹¹ which may be identical ordifferent, whilst the above-mentioned alkyl or alkylene moieties may bebranched or unbranched, or a tautomer thereof, a stereoisomer thereof, amixture thereof, or a salt thereof.
 2. The compound according to claim1, wherein R¹ denotes phenyl, naphthyl, pyrrolyl, furanyl, thienyl,pyridinyl, indolyl, benzofuranyl, benzo-thiophenyl, quinolinyl,isoquinolinyl, or pyrrolyl, furanyl, thienyl, pyridinyl, in each ofwhich 1 or 2 CH are replaced by N, or indolyl, benzofuranyl,benzothiophenyl, quinolinyl, isoquinolinyl, in each of which 1 or 2 CHare replaced by N, or indolinyl, 2-oxo-2,3-dihydro-indolyl,1-oxo-2,3-dihydro-isoindolyl, 2-oxo-2,3-dihydro-benzoimidazolyl,pyrazolo[1,5-a]pyrimidinyl,7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidinyl,[1,2,4]triazolo[1,5-a]pyrimidinyl, 4-oxo-3,4-dihydro-quinazolinyl,tetrahydroquinolinyl, wherein the above-mentioned aromatic andheteroaromatic groups are optionally substituted with one or more,preferably one to four, substituents R⁴ and wherein 2 adjacent C-atomsare optionally substituted with R⁵ and R⁶, or a pharmaceuticallyacceptable salt thereof.
 3. The compound according to claim 1, whereinR¹ denotes phenyl, naphthyl, furanyl, thienyl, pyrazolyl, oxazolyl,thiazolyl, isothiazolyl, [1,2,5]-thiadiazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, benzofuranyl, indolyl, indolinyl,2-oxo-2,3-dihydro-indolyl, 1-oxo-2,3-dihydro-isoindolyl, indazolyl,benzimidazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl, benzoxazolyl,benzotriazolyl, benzothiazolyl, pyrazolo[1,5-a]pyrimidinyl,7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidinyl, quinoxalinyl, quinolinyl,isoquinolinyl, quinazolinyl, 4-oxo-3,4-dihydro-quinazolinyl,naphthyridinyl, and 1,2,3,4-tetrahydroquinolinyl, each of these groupsis optionally substituted with one or more, preferably one to four,substituents R⁴ and/or at 2 adjacent C-atoms with R⁵ and R⁶, or apharmaceutically acceptable salt thereof.
 4. The compound according toclaim 1, wherein R¹ denotes phenyl, furanyl, thienyl, pyrazolyl,thiazolyl, pyridinyl, benzofuranyl, indolyl, indolinyl,2-oxo-2,3-dihydro-1H-indolyl, 1-oxo-2,3-dihydro-1H-isoindolyl,indazolyl, benzimidazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl,benzotriazolyl, benzothiazolyl, quinoxalinyl, quinolinyl, isoquinolinyl,4-oxo-3,4-dihydro-quinazolinyl, and 1,2,3,4-tetrahydroquinolinyl, eachof these groups is optionally substituted with one to four substituentsR⁴ and/or at 2 adjacent C-atoms with R⁵ and R⁶, or a pharmaceuticallyacceptable salt thereof.
 5. The compound according to claim 1, whereinR¹ denotes phenyl, benzofuranyl, indolyl, 2-oxo-2,3-dihydro-1H-indolyl,indazolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, quinoxalinyl,quinolinyl, and 1,2,3,4-tetrahydroquinolinyl, each of these groups isoptionally substituted with one, two, or three substituents R⁴ oroptionally substituted with one or two substituents R⁴ and/or at 2adjacent C-atoms with R⁵ and R⁶, or a pharmaceutically acceptable saltthereof.
 6. The compound according to claim 1, wherein R² denotesphenyl, naphthyl, pyrrolyl, furanyl, thienyl, pyridinyl, indolyl,benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, or pyrrolyl,furanyl, thienyl, pyridinyl wherein 1 or 2 CH are replaced by N, orindolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, ineach of which 1 or 2 CH are replaced by N, while all the above-mentionedaromatic and heteroaromatic rings are optionally substituted with one tofour R⁷, or a pharmaceutically acceptable salt thereof.
 7. The compoundaccording to claim 1, wherein R² denotes phenyl, naphthyl, furanyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indoly, benzimidazolyl,benzoxazolyl, quinolinyl, or isoquinolinyl, each of these groups may besubstituted with one, two, or three R⁷, or a pharmaceutically acceptablesalt thereof.
 8. The compound according to claim 1, wherein R² denotesphenyl, naphthyl, or pyridinyl that are optionally substituted with one,two, or three R⁷, or a pharmaceutically acceptable salt thereof.
 9. Thecompound according to claim 1, wherein R² denotes phenyl optionallysubstituted with one or two R⁷, or a pharmaceutically acceptable saltthereof.
 10. The compound according to claim 1, wherein R⁴ denotesfluorine, chlorine, bromine, C₁₋₄-alkyl, hydroxy, C₁₋₄-alkyloxy, nitro,amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino, pyrrolidin-1-yl,2-oxo-pyrrolidin-1-yl, piperidin-1-yl, 2-oxo-piperidin-1-yl,morpholin-4-yl, 3-oxo-morpholin-4-yl, piperazin-1-yl,2-oxo-piperazin-1-yl, 3-oxo-piperazin-1-yl,4-(C₁₋₃-alkyl)-piperazin-1-yl, 4-(C₁₋₄-alkylcarbonyl)-piperazin-1-yl,4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,4-(C₁₋₄-alkyloxycarbonyl)-piperazin-1-yl, 4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl, 2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl, C₁₋₃-alkyl-carbonylamino,(het)arylcarbonylamino, (het)aryl-C₁₋₃-alkyl-carbonyl-amino,C₁₋₃-alkyloxy-carbonylamino, aminocarbonylamino,C₁₋₃-alkyl-amino-carbonylamino, di-(C₁₋₃-alkyl)aminocarbonylamino,pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamino,morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino,4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonylamino, C₁₋₃-alkyl-sulfonylamino,(het)arylsulfonylamino, (het)aryl-C₁₋₃-alkyl-sulfonylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-carbonylamino, N—(C₁₋₃-alkyl)-(het)arylcarbonylamino, N—(C₁₋₃-alkyl)-(het) aryl-C₁₋₃-alkyl-carbonylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyloxy-carbonylamino,N-(aminocarbonyl)-C₁₋₃-alkylamino,N—(C₁₋₃-alkyl-aminocarbonyl)-C₁₋₃-alkylamino,N-[di-(C₁₋₃-alkyl)aminocarbonyl]-C₁₋₃-alkylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-sulfonylamino,N—(C₁₋₃-alkyl)-(het)arylsulfonylamino,N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkyl-sulfonylamino, oxo-imidazolidinyl,2,4-dioxo-imidazolidinyl, 2,5-dioxo-imidazolidin-1-yl,2-oxo-hexahydropyrimidin-1-yl, wherein the nitrogen atom in position 3of the aforementioned groups is optionally substituted with methyl,1,1-dioxo-[1,2]thiazinan-2-yl, cyano, carboxy, C₁₋₃-alkyloxy-carbonyl,aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,pyrrolidin-1-yl-carbonyl, 2-(methoxymethyl)-pyrrolidin-1-yl-carbonyl,3-(methoxymethyl)-pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,morpholin-4-yl-carbonyl, piperazin-1-yl-carbonyl,4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl, (het)arylaminocarbonyl,N—(C₁₋₃-alkyl)-(het)arylaminocarbonyl,(het)aryl-C₁₋₃-alkylaminocarbonyl,N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkylaminocarbonyl, C₁₋₄-alkyl-carbonyl,(het)aryl-carbonyl, C₁₋₃-alkylcarbonyl-C₁₋₃-alkyl, carboxy-C₁₋₃-alkyl,C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyl, cyano-C₁₋₃-alkyl,aminocarbonyl-C₁₋₃-alkyl, C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl,pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl, piperidin-1-yl-carbonyl-C₁₋₃-alkyl,morpholin-4-yl-carbonyl-C₁₋₃-alkyl, piperazin-1-yl-carbonyl-C₁₋₃-alkyl,4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl-C₁₋₃-alkyl,carboxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyloxy,cyano-C₁₋₃-alkyloxy, aminocarbonyl-C₁₋₃-alkyloxy,C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyloxy,di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy,pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl-oxy,piperidin-1-yl-carbonyl-C₁₋₃-alkyloxy,morpholin-4-yl-carbonyl-C₁₋₃-alkyl-oxy,piperazin-1-yl-carbonyl-C₁₋₃-alkyloxy,4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl-C₁₋₃-alkyloxy,hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,pyrrolidin-1-yl-C₁₋₃-alkyl, 2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl,piperidin-1-yl-C₁₋₃-alkyl, 2-oxo-piperidin-1-yl-C₁₋₃-alkyl,morpholin-4-yl-C₁₋₃-alkyl, (methyl-morpholin-4-yl)-C₁₋₃-alkyl,(dimethyl-morpholin-4-yl)-C₁₋₃-alkyl, 3-oxo-morpholin-4-yl-C₁₋₃-alkyl,piperazin-1-yl-C₁₋₃-alkyl, 2-oxo-piperazin-1-yl-C₁₋₃-alkyl,3-oxo-piperazin-1-yl-C₁₋₃-alkyl,4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl, (het)arylcarbonylamino-C₁₋₃-alkyl,hydroxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-C₁₋₃-alkyloxy,C₁₋₃-alkylsulfanyl-C₁₋₃-alkyloxy, C₁₋₃-alkylsulfinyl-C₁₋₃-alkyloxy,C₁₋₃-alkylsulfonyl-C₁₋₃-alkyloxy, amino-C₁₋₃-alkyloxy,C₁₋₃-alkylamino-C₁₋₃-alkyloxy, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyloxy,pyrrolidin-1-yl-C₁₋₃-alkyloxy, 2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyloxy,piperidin-1-yl-C₁₋₃-alkyloxy, 2-oxo-piperidin-1-yl-C₁₋₃-alkyloxy,morpholin-4-yl-C₁₋₃-alkyloxy, 3-oxo-morpholin-4-yl-C₁₋₃-alkyloxy,piperazin-1-yl-C₁₋₃-alkyloxy, 2-oxo-piperazin-1-yl-C₁₋₃-alkyloxy,3-oxo-piperazin-1-yl-C₁₋₃-alkyloxy,4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyloxy,2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyloxy,3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyloxy, C₁₋₃-alkylsulfanyl,C₁₋₃-alkysulfinyl, C₁₋₃-alkylsulfonyl, (het)arylsulfonyl, aminosulfonyl,C₁₋₃-alkyl-aminosulfonyl, di-(C₁₋₃-alkyl)-aminosulfonyl,pyrrolidin-1-yl-sulfonyl, piperidin-1-yl-sulfonyl,morpholin-4-yl-sulfonyl, piperazin-1-yl-sulfonyl,4-(C₁₋₃-alkyl)-piperazin-1-yl-sulfonyl, difluoromethyl, trifluoromethyl,difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoro-1-hydroxyethyl,2,2,2-trifluoro-1-hydroxy-1-methylethyl,2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyloxy, C₃₋₆-cycloalkyl-C₁₋₃-alkyl,C₃₋₆-cycloalkyl-C₁₋₃-alkyloxy, (het)aryl, (het)aryloxy,(het)aryl-C₁₋₃-alkyl, (het)aryl-C₁₋₃-alkyloxy, (het)aryloxy-C₁₋₃-alkyl,or tetrahydrofuran-3-yl-oxy, tetrahydropyran-3-yl-oxy,tetrahydropyran-4-yl-oxy, tetra-hydrofuranyl-C₁₋₃-alkyloxy,tetrahydropyranyl-C₁₋₃-alkyloxy, thietan-3-yloxy, wherein theabove-mentioned (het)aryl groups are phenyl, naphthyl, or pyrrolyl,furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl,quinolinyl, isoquinolinyl, or pyrrolyl, furanyl, thienyl, imidazolyl,pyridyl, wherein 1 or 2 CH are replaced by N, or indolyl, benzofuranyl,benzothiophenyl, quinolinyl, isoquinolinyl, wherein 1 to 3 CH arereplaced by N, or 1,2-dihydro-2-oxo-pyridinyl,1,4-dihydro-4-oxo-pyridinyl, 2,3-dihydro-3-oxo-pyridazinyl,1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl, 1,2-dihydro-2-oxo-pyrimidinyl,3,4-dihydro-4-oxo-pyrimidinyl, 1,2,3,4-tetrahydro-2,4-dioxo-pyrimidinyl,1,2-dihydro-2-oxo-pyrazinyl, 1,2,3,4-tetrahydro-2,3-dioxo-pyrazinyl,2,3-dihydro-2-oxo-indolyl, 2,3-dihydrobenzofuranyl,2,3-dihydro-2-oxo-1H-benzimidazolyl, 2,3-dihydro-2-oxo-benzoxazolyl,1,2-dihydro-2-oxo-quinolinyl, 1,4-dihydro-4-oxo-quino-linyl,1,2-dihydro-1-oxo-isoquinolinyl, 1,4-dihydro-4-oxo-cinnolinyl,1,2-dihydro-2-oxo-quinazolinyl, 1,4-dihydro-4-oxo-quinazolinyl,1,2,3,4-tetrahydro-2,4-dioxo-quinazolinyl,1,2-dihydro-2-oxoquinoxalinyl, 1,2,3,4-tetrahydro-3-oxo-quinoxalinyl,1,2,3,4-tetrahydro-2,3-dioxo-quinoxalinyl,1,2-dihydro-1-oxo-phthalazinyl,1,2,3,4-tetrahydro-1,4-dioxo-phthalazinyl, chromanyl, coumarinyl,2,3-dihydro-benzo[1,4]dioxinyl, 3,4-dihydro-3-oxo-2H-benzo[1,4]oxazinyl,and wherein all the above-mentioned (het)aryl groups are optionallysubstituted with 1, 2, or 3 R¹¹ which may be identical or different, ora pharmaceutically acceptable salt thereof.
 11. The compound accordingto claim 1, wherein R⁴ denotes fluorine, chlorine, bromine, C₁₋₄-alkyl,hydroxy, C₁₋₄-alkyloxy, thietan-3-yloxy, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)amino, pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl,piperidin-1-yl, 2-oxo-piperidin-1-yl, morpholin-4-yl,3-oxo-morpholin-4-yl, piperazin-1-yl, 2-oxo-piperazin-1-yl,3-oxo-piperazin-1-yl, 4-(C₁₋₃-alkyl)-piperazin-1-yl,4-(C₁₋₄-alkylcarbonyl)-piperazin-1-yl,4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,4-(C₁₋₄-alkyloxycarbonyl)-piperazin-1-yl, 4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl, 2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl, C₁₋₃-alkyl-carbonylamino,(het)arylcarbonylamino, (het)aryl-C₁₋₃-alkyl-carbonyl-amino,C₁₋₃-alkyloxy-carbonylamino, aminocarbonylamino,C₁₋₃-alkyl-amino-carbonylamino, di-(C₁₋₃-alkyl)aminocarbonylamino,pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamino,morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino,4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonylamino, 2-oxo-imidazolidinyl,1,1-dioxo-[1,2]thiazinanyl, cyano, carboxy, C₁₋₃-alkyloxy-carbonyl,aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,pyrrolidin-1-yl-carbonyl, 2-(methoxymethyl)-pyrrolidin-1-yl-carbonyl,3-(methoxymethyl)-pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,morpholin-4-yl-carbonyl, piperazin-1-yl-carbonyl,4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl,N—(C₁₋₃-alkyl)-(het)arylaminocarbonyl, N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃alkylaminocarbonyl, C₁₋₄-alkyl carbonyl, (het)aryl-carbonyl,C₁₋₃-alkylcarbonyl-C₁₋₃-alkyl, hydroxy-C₁₋₃-alkyl,C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl, pyrrolidin-1-yl-C₁₋₃-alkyl,2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl, morpholin-4-yl-C₁₋₃-alkyl,C₁₋₄-alkylsulfonyl, aminosulfonyl, C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl,(het)arylcarbonylamino-C₁₋₃-alkyl, hydroxy-C₁₋₃-alkyloxy,C₁₋₃-alkyloxy-C₁₋₃-alkyloxy, difluoromethyl, trifluoromethyl,difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoro-1-hydroxyethyl,2,2,2-trifluoro-1-hydroxy-1-methylethyl,2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl, (het)aryl,(het)aryl-C₁₋₃-alkyl or (het)aryloxy, wherein the above-mentioned(het)aryl groups are phenyl, naphthyl, pyrrolyl, furanyl, thienyl,pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl, andisoquinolinyl, or pyrrolyl, furanyl, thienyl, imidazolyl, or pyridyl,wherein 1 or 2 CH are replaced by N, or indolyl, benzofuranyl,benzothiophenyl, quinolinyl, or isoquinolinyl, wherein 1 to 3 CH arereplaced by N, and wherein the above-mentioned (het)aryl groups may besubstituted with 1, 2, or 3 R¹¹ which may be identical or different, ora pharmaceutically acceptable salt thereof.
 12. The compound accordingto claim 1, wherein R⁴ denotes fluorine, chlorine, C₁₋₄-alkyl,difluoromethyl, trifluoromethyl, hydroxy, C₁₋₄-alkyloxy,difluoromethoxy, trifluoromethoxy, thietan-3-yloxy, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino, pyrrolidin-1-yl, piperidin-1-yl,morpholin-4-yl, C₁₋₃-alkyl-carbonylamino, C₁₋₄-alkylcarbonyl, carboxy,cyano, C₁₋₃-alkoxycarbonyl, amino-carbonyl, C₁₋₃-alkyl-aminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, 2-oxo-pyrrolidin-1-yl,hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,morpholin-4-yl-C₁₋₃-alkyl, C₁₋₃-alkylcarbonyl-C₁₋₃-alkyl,C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl, 1,1-dioxo-[1,2]thiazinan-2-yl,2-oxo-imidazolidinyl, C₁₋₄-alkylsulfonyl, aminosulfonyl, phenyl,pyrazolyl, oxazolyl, [1,2,4]oxadiazol-3-yl, or tetrazol-1-yl, while thearomatic and heteroaromatic groups listed may be substituted with 1, 2,or 3 groups R¹¹ which may be identical or different, or apharmaceutically acceptable salt thereof.
 13. The compound according toclaim 1, wherein R⁴ denotes fluorine, chlorine, methyl, ethyl,iso-butyl, tert-butyl, difluoromethyl, trifluoromethyl, hydroxy,methoxy, tert-butyloxy, thietan-3-yloxy, amino, methylamino,acetylamino, hydroxymethyl, acetylaminomethyl, carboxy, cyano,methoxycarbonyl, aminocarbonyl, methylaminocarbonyl,2-oxo-pyrrolidin-1-yl, methylcarbonyl, 2-oxo-imidazolidinyl,methylsulfonyl, aminosulfonyl, phenyl, pyrazol-3-yl, oxazol-5-yl,5-methyl-[1,2,4]oxadiazol-3-yl, tetrazol-1-yl, or tetrazol-5-yl, or apharmaceutically acceptable salt thereof.
 14. The compound according toclaim 1, wherein R⁷ denotes halogen, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, hydroxy, C₁₋₄-alkyloxy, nitro, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)amino, pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl,piperidin-1-yl, 2-oxo-piperidin-1-yl, morpholin-4-yl,3-oxo-morpholin-4-yl, piperazin-1-yl, 2-oxo-piperazin-1-yl,3-oxo-piperazin-1-yl, 4-(C₁₋₄-alkylcarbonyl)-piperazin-1-yl,4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,4-(C₁₋₄-alkyloxycarbonyl)-piperazin-1-yl,4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl,2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl, C₁₋₃-alkyl-carbonylamino,(het)aryl-carbonylamino, C₁₋₃-alkyloxy-carbonylamino,aminocarbonylamino, C₁₋₃-alkyl-aminocarbonylamino,di-(C₁₋₃-alkyl)aminocarbonylamino, pyrrolidin-1-yl-carbonylamino,piperidin-1-yl-carbonylamino, morpholin-4-yl-carbonylamino,C₁₋₃-alkyl-sulfonylamino, C₁₋₃-alkyl-amino-sulfonylamino,di-(C₁₋₃-alkyl)amino-sulfonylamino, pyrrolidin-1-yl-sulfonyl-amino,piperidin-1-yl-sulfonylamino, morpholin-4-yl-sulfonylamino,(het)aryl-sulfonylamino, N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-carbonylamino,N—(C₁₋₃-alkyl)-(het) arylcarbonylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyloxy-carbonylamino,N-(aminocarbonyl)-C₁₋₃-alkylamino,N—(C₁₋₃-alkyl-aminocarbonyl)-C₁₋₃-alkylamino,N-[di-(C₁₋₃-alkyl)aminocarbonyl]-C₁₋₃-alkylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-sulfonylamino,N—(C₁₋₃-alkyl)-(het)arylsulfonylamino, cyano, carboxy,C₁₋₃-alkyloxy-carbonyl, aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, pyrrolidin-1-yl-carbonyl,piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl,piperazin-1-yl-carbonyl, 4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl,(het)arylaminocarbonyl, N—(C₁₋₃-alkyl)-(het)arylaminocarbonyl,(het)aryl-C₁₋₃-alkylaminocarbonyl,N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkylaminocarbonyl, C₁₋₄-alkyl-carbonyl,(het)aryl-carbonyl, carboxy-C₁₋₃-alkyl,C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyl, cyano-C₁₋₃-alkyl,aminocarbonyl-C₁₋₃-alkyl, C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl,pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl, piperidin-1-yl-carbonyl-C₁₋₃-alkyl,morpholin-4-yl-carbonyl-C₁₋₃-alkyl, carboxy-C₁₋₃-alkyloxy,C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyloxy, cyano-C₁₋₃-alkyloxy,aminocarbonyl-C₁₋₃-alkyloxy, C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyloxy,di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy,pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl-oxy,piperidin-1-yl-carbonyl-C₁₋₃-alkyloxy,morpholin-4-yl-carbonyl-C₁₋₃-alkyl-oxy, hydroxy-C₁₋₃-alkyl,C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl, pyrrolidin-1-yl-C₁₋₃-alkyl,2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl, piperidin-1-yl-C₁₋₃-alkyl,2-oxo-piperidin-1-yl-C₁₋₃-alkyl, morpholin-4-yl-C₁₋₃-alkyl,3-oxo-morpholin-4-yl-C₁₋₃-alkyl, 3-oxo-piperazin-1-yl-C₁₋₃-alkyl,3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl, arylcarbonylamino-C₁₋₃-alkyl,hydroxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-C₁₋₃-alkyloxy,C₁₋₃-alkylsulfanyl-C₁₋₃-alkyloxy, C₁₋₃-alkylsulfinyl-C₁₋₃-alkyloxy,C₁₋₃-alkylsulfonyl-C₁₋₃-alkyloxy, amino-C₁₋₃-alkyloxy,C₁₋₃-alkylamino-C₁₋₃-alkyloxy, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyloxy,pyrrolidin-1-yl-C₁₋₃-alkyloxy, 2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyloxy,piperidin-1-yl-C₁₋₃-alkyloxy, 2-oxo-piperidin-1-yl-C₁₋₃-alkyloxy,morpholin-4-yl-C₁₋₃-alkyloxy, 3-oxo-morpholin-4-yl-C₁₋₃-alkyloxy,3-oxo-piperazin-1-yl-C₁₋₃-alkyloxy,3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyloxy, C₁₋₃-alkylsulfanyl,C₁₋₃-alkysulfinyl, C₁₋₃-alkylsulfonyl, (het)arylsulfonyl,trifluoromethylsulfinyl, trifluoromethylsulfonyl, aminosulfonyl,C₁₋₃-alkyl-aminosulfonyl, di-(C₁₋₃-alkyl)-aminosulfonyl,pyrrolidin-1-yl-sulfonyl, piperidin-1-yl-sulfonyl,morpholin-4-yl-sulfonyl, difluoromethyl, trifluoromethyl,difluoromethoxy, trifluoromethoxy, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyloxy,C₃₋₆-cycloalkyl-C₁₋₃-alkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyloxy, (het)aryl,(het)aryloxy, (het)aryl-C₁₋₃-alkyl, (het)aryl-C₁₋₃-alkyloxy,(het)aryloxy-C₁₋₃-alkyl, or tetrahydrofuran-3-yloxy,tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy,tetrahydrofuranyl-C₁₋₃-alkyloxy, tetrahydropyranyl-C₁₋₃-alkyloxy,wherein the above-mentioned (het)aryl is phenyl, naphthyl, pyrrolyl,furanyl, thienyl, pyridyl, or pyrrolyl, furanyl, thienyl, imidazolyl,pyridyl, in which 1 or 2 CH are replaced by N, and wherein theabove-mentioned (het)aryl groups are optionally substituted with one ortwo R¹¹ which may be identical or different, or a pharmaceuticallyacceptable salt thereof.
 15. The compound according to claim 1, whereinR⁷ denotes fluorine, chlorine, bromine, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, hydroxy, C₁₋₄-alkyloxy, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)amino, C₁₋₃-alkyl-carbonylamino,C₁₋₃-alkyloxy-carbonylamino, aminocarbonylamino,C₁₋₃-alkyl-aminocarbonylamino, di-(C₁₋₃-alkyl)aminocarbonylamino,C₁₋₃-alkyl-sulfonylamino, N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-carbonylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-sulfonylamino, cyano, carboxy,C₁₋₃-alkyloxy-carbonyl, aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, pyrrolidin-1-yl-carbonyl,piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl, carboxy-C₁₋₃-alkyl,C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyl, cyano-C₁₋₃-alkyl,aminocarbonyl-C₁₋₃-alkyl, C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl, carboxy-C₁₋₃-alkyloxy,C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyloxy, cyano-C₁₋₃-alkyloxy,hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl, hydroxy-C₁₋₃-alkyloxy,C₁₋₃-alkyloxy-C₁₋₃-alkyloxy, C₁₋₃-alkylsulfonyl,trifluoromethylsulfonyl, aminosulfonyl, C₁₋₃-alkyl-aminosulfonyl,di-(C₁₋₃-alkyl)-aminosulfonyl, difluoromethyl, trifluoromethyl,difluoromethoxy, trifluoromethoxy, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyloxy,tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,tetrahydropyran-4-yloxy, tetrahydrofuranyl-C₁₋₃-alkyloxy,tetrahydropyranyl-C₁₋₃-alkyloxy, or phenyl or phenoxy that areoptionally substituted with one or two identical or different R¹¹, or apharmaceutically acceptable salt thereof.
 16. The compound according toclaim 1, wherein R⁷ denotes fluorine, chlorine, bromine, C₁₋₄-alkyl,trifluoromethyl, hydroxy, C₁₋₄-alkyloxy, trifluoromethoxy, phenoxy,amino-C₁₋₃-alkyl, carboxy, cyano, C₁₋₃-alkoxycarbonyl, aminocarbonyl,C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl, or phenyl, or apharmaceutically acceptable salt thereof.
 17. The compound according toclaim 1, wherein R⁷ denotes fluorine, chlorine, bromine, methyl,isopropyl, trifluoromethyl, hydroxy, methoxy, trifluoromethoxy, phenoxy,aminomethyl, carboxy, methoxycarbonyl, aminocarbonyl, or phenyl, or apharmaceutically acceptable salt thereof.
 18. (canceled)
 19. Thecompound according to claim 1 wherein: R¹ denotes phenyl, naphthyl,furanyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, indolyl,indolinyl, 2-oxo-2,3-dihydro-indolyl, 1-oxo-2,3-dihydro-isoindolyl,indazolyl, benzimidazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl,benzoxazolyl, benzotriazolyl, benzothiazolyl,pyrazolo[1,5-a]pyrimidinyl,7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidinyl, quinoxalinyl, quinolinyl,isoquinolinyl, quinazolinyl, 4-oxo-3,4-dihydro-quinazolinyl,naphthyridinyl, and 1,2,3,4-tetrahydroquinolinyl, each of these groupsis optionally substituted with one or more, preferably one to four,substituents R⁴ and/or at 2 adjacent C-atoms with R⁵ and R⁶; R² denotesphenyl, naphthyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, indoly, benzimidazolyl, benzoxazolyl, quinolinyl, orisoquinolinyl, each of these groups is optionally substituted with one,two, or three R⁷; R⁴ denotes fluorine, chlorine, bromine, C₁₋₄-alkyl,hydroxy, C₁₋₄-alkyloxy, thietan-3-yloxy, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)amino, pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl,piperidin-1-yl, 2-oxo-piperidin-1-yl, morpholin-4-yl,3-oxo-morpholin-4-yl, piperazin-1-yl, 2-oxo-piperazin-1-yl,3-oxo-piperazin-1-yl, 4-(C₁₋₃-alkyl)-piperazin-1-yl,4-(C₁₋₄-alkylcarbonyl)-piperazin-1-yl,4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,4-(C₁₋₄-alkyloxycarbonyl)-piperazin-1-yl, 4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl, 2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl, C₁₋₃-alkyl-carbonylamino,(het)arylcarbonylamino, (het)aryl-C₁₋₃-alkyl-carbonyl-amino,C₁₋₃-alkyloxy-carbonylamino, aminocarbonylamino,C₁₋₃-alkyl-amino-carbonylamino, di-(C₁₋₃-alkyl)aminocarbonylamino,pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamino,morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino,4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonylamino, 2-oxo-imidazolidinyl,1,1-dioxo-[1,2]thiazinanyl, cyano, carboxy, C₁₋₃-alkyloxy-carbonyl,aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,pyrrolidin-1-yl-carbonyl, 2-(methoxymethyl)-pyrrolidin-1-yl-carbonyl,3-(methoxymethyl)-pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,morpholin-4-yl-carbonyl, piperazin-1-yl-carbonyl,4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl,N—(C₁₋₃-alkyl)-(het)arylaminocarbonyl,N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkylaminocarbonyl, C₁₋₄-alkyl-carbonyl,(het)aryl-carbonyl, C₁₋₃-alkylcarbonyl-C₁₋₃-alkyl, hydroxy-C₁₋₃-alkyl,C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl, pyrrolidin-1-yl-C₁₋₃-alkyl,2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl, morpholin-4-yl-C₁₋₃-alkyl,C₁₋₃-alkylsulfonyl, aminosulfonyl, C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl,(het)arylcarbonylamino-C₁₋₃-alkyl, hydroxy-C₁₋₃-alkyloxy,C₁₋₃-alkyloxy-C₁₋₃-alkyloxy, difluoromethyl, trifluoromethyl,difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoro-1-hydroxyethyl,2,2,2-trifluoro-1-hydroxy-1-methylethyl,2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl, (het)aryl,(het)aryl-C₁₋₃-alkyl or (het)aryloxy, wherein the above-mentioned(het)aryl groups are phenyl, naphthyl, pyrrolyl, furanyl, thienyl,pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl, andisoquinolinyl, or pyrrolyl, furanyl, thienyl, imidazolyl, or pyridylwherein 1 or 2 CH are replaced by N, or indolyl, benzofuranyl,benzothiophenyl, quinolinyl, or isoquinolinyl wherein 1 to 3 CH arereplaced by N, and wherein the above-mentioned (het)aryl groups may besubstituted with 1, 2, or 3 R¹¹ which may be identical or different; R⁵and R⁶ form a methylenedioxy, difluoromethylenedioxy, ethylenedioxy,propylene, or butylene group; R⁷ denotes fluorine, chlorine, bromine,C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, hydroxy, C₁₋₄-alkyloxy, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino, C₁₋₃-alkyl-carbonylamino,C₁₋₃-alkyloxy-carbonylamino, aminocarbonylamino,C₁₋₃-alkyl-aminocarbonylamino, di-(C₁₋₃-alkyl)aminocarbonylamino,C₁₋₃-alkyl-sulfonylamino, N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-carbonylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-sulfonylamino, cyano, carboxy,C₁₋₃-alkyloxy-carbonyl, aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, pyrrolidin-1-yl-carbonyl,piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl, carboxy-C₁₋₃-alkyl,C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyl, cyano-C₁₋₃-alkyl,aminocarbonyl-C₁₋₃-alkyl, C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl, carboxy-C₁₋₃-alkyloxy,C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyloxy, cyano-C₁₋₃-alkyloxy,hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl, hydroxy-C₁₋₃-alkyloxy,C₁₋₃-alkyloxy-C₁₋₃-alkyloxy, C₁₋₃-alkylsulfonyl,trifluoromethylsulfonyl, aminosulfonyl, C₁₋₃-alkyl-aminosulfonyl,di-(C₁₋₃-alkyl)-aminosulfonyl, difluoromethyl, trifluoromethyl,difluoromethoxy, trifluoromethoxy, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyloxy,tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,tetrahydropyran-4-yloxy, tetrahydrofuranyl-C₁₋₃-alkyloxy,tetrahydropyranyl-C₁₋₃-alkyloxy, or phenyl or phenoxy that areoptionally substituted with one or two identical or different R¹¹. R¹¹denotes fluorine, methyl, methoxy, cyano, or acetylamino; or apharmaceutically acceptable salt thereof.
 20. The compound of formula Ia

wherein the residue R² occupies the endo (=trans to the NCOR¹ residueand cis to the ethylene bridge) position of the bicyclic structure andwherein R¹ and R² are defined as in claim 1, or a pharmaceuticallyacceptable salt thereof.
 21. The compound of formula Ia

wherein the residue R² occupies the endo (=trans to the NCOR¹ residueand cis to the ethylene bridge) position of the bicyclic structure andwherein R¹ and R² are defined as in claim 6, respectively, or apharmaceutically acceptable salt thereof.
 22. (canceled)
 23. (canceled)24. A physiologically acceptable salt of a compound according to claim 1with inorganic or organic acids or bases.
 25. A pharmaceuticalcomposition containing a compound according to claim 1, or aphysiologically acceptable salt with inorganic or organic acids orbases, optionally together with one or more inert carriers and/ordiluents.
 26. A method of treating or preventing a disease or conditionwhich can be influenced by inhibiting the enzyme 11β-hydroxysteroiddehydrogenase (HSD) 1, the method comprising administering to a patientin need thereof the compound of claim 1, or a physiologically acceptablesalt with inorganic or organic acids or bases.
 27. (canceled)
 28. Aprocess for preparing a compound of the general formula I according toclaim 1, or a physiologically acceptable salt with inorganic or organicacids or bases, characterized in that a compound of formula II

wherein the group R² is defined as in claim 1, is reacted with acompound of formula R¹—CO—Y, optionally prepared in situ from thecorresponding carboxylic acid, wherein R¹ is defined as in claim 1 and Yis a leaving group and denotes fluorine, chlorine, bromine, cyano,C₁₋₄-alkoxy, C₂₋₄-alkenyloxy, C₂₋₄-alky-nyloxy, C₁₋₄-alkylsulfanyl,arylotriazoloxy, heteroarylotriazoloxy, hetero-N-aryl, succinyl-N-oxy,C₁₋₄-alkylcarbonyloxy, di-(C₁₋₄-alkyl)-aminocarbonyloxy,pyrrolyl-carbonyloxy, piperidinylcarbonyloxy, morpholinylcarbonyloxy,tri-(C₁₋₄-alkyl)-carb-amimidoyloxy,N,N,N′,N′-tetra-(C₁₋₄-alkyl)uronium-O-yl, N,N′-dicyclohexyluron-O-yl,di-(C₁₋₄-alkyloxy)-phosphoryloxy, di-(di-C₁₋₄-alkylamino)-phosphoryloxy,dipyrrolidinyl-phosphoryloxy, aryloxy, arylsulfanyl, heterosulfanyl, orheteroaryloxy, while the alkyl, alkenyl, and alkynyl groups mentioned inthe definition of the above groups, optionally are mono- orpolysubstituted with fluorine, chlorine, C₁₋₃-alkyl, or C₁₋₃-alkoxy,while the aryl groups mentioned in the definition of the above groupsdenote phenyl or naphthyl groups and the heteroaryl groups mentioned inthe definition of the above groups denote pyridinyl, pyrimidinyl,triazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, whilst both thearyl and heteroaryl groups optionally are mono- or polysubstitutedindependently with fluorine, chlorine, bromine, C₁₋₃-alkyl,C₁₋₃-alkyloxy, nitro, cyano, or di-(C₁₋₃-alkyl)amino groups, optionallyin the presence of a base or another additive.